Adenocarcinoma of the stomach was the leading cause of cancer-related death worldwide through most of the 20th century. It now ranks second only to lung cancer; an estimated 952,000 new cases are diagnosed annually, and an estimated 723,000 deaths (10% of all cancer deaths) worldwide.1 In the West, the incidence of gastric cancer has decreased, potentially because of changes in diet, food preparation, and other environmental factors. The declining incidence has been dramatic in the United States in all age groups except between 25 and 39 years (noncardia cancers), ranked sixth as a cause of cancer-related death during the period of 2000 to 2006. It is estimated that in 2009, 21,130 new gastric cancer cases were diagnosed in the United States, with approximately 10,600 deaths.2 Data was updated for 2018 where an estimated 26,240 new cases will be diagnosed in the United States, with approximately 10,880 deaths. Prognosis remains poor except in a few countries where early screening is feasible (East Asia). The decline in incidence has been limited to noncardia gastric cancers and intestinal type.3 The number of newly diagnosed cases of proximal gastric and esophagogastric junction (EGJ) adenocarcinomas has increased sixfold since the mid-1980s, paralleling Barrett dysplasia geography. These proximal tumors are thought to be biologically more aggressive and more complex to treat. The only chance of cure is complete surgical resection. However, even after what is believed to be a “curative” gastrectomy, disease recurs in the majority of patients. Efforts to improve these poor results have focused on developing effective pre- and postoperative systemic and regional adjuvant therapies.
The stomach begins at the gastroesophageal junction and ends at the pylorus (Fig. 53.1). Cancers arising from the proximal greater curvature may directly involve the splenic hilum and tail of pancreas, whereas more distal tumors may invade the transverse colon. Proximal cancers may extend into the diaphragm, spleen, or the left lateral segment of the liver. A recent study reported on the potential benefits and harms of complete resection even when the tumor invades adjacent abdominal visceral structures (pT4b).4 In this large multicenter cohort series of 2,208 patients who underwent curative intent resection, 206 patients had pT4b tumors and 112 underwent resection of adjacent organs as part of en bloc gastric cancer resection. The 5-year overall survival (OS) rate for this group of patients was 27.2%, suggesting that patients do have a chance at long-term survival if their tumor can be removed en bloc with involved adjacent organs, thereby supporting the role of multivisceral resection if required and technically feasible.
The blood supply to the stomach is extensive and is based on vessels arising from the celiac axis (see Fig. 53.1). The right gastric artery arises from the hepatic artery proper (50% to 68%), from the left hepatic artery (29% to 40%), or from the common hepatic artery (3.2%). The left gastric artery originates from the celiac axis directly (90%) and may arise from the common hepatic artery (2%), splenic artery (4%), or aorta or from the superior mesenteric artery (3%). Both right and left gastric arteries course along the lesser curvature. Along the greater curvature are the right gastroepiploic artery, which originates from the gastroduodenal artery at the inferior border of the proximal duodenum (rarely from the superior mesenteric artery), and the left gastroepiploic artery (highly variable artery), branching from the distal (72%), inferior, middle splenic artery laterally. The short gastric arteries (vasa brevia, five to seven separate vessels) arise directly from the splenic artery or the left gastroepiploic artery. The posterior (dorsal) gastric artery (17% to 68%) may arise from the splenic artery to supply the distal esophagus, cardia, and fundus. The preservation of any of these vessels in the course of a subtotal gastrectomy for carcinoma is not necessary, and the most proximal few centimeters of remaining stomach are well supplied by collateral flow from the lower segmental esophageal arterial arcade. The rich submucosal blood supply of the stomach is an important factor in its ability to heal rapidly and produce a low incidence of anastomotic disruption following radical gastric resection. The venous drainage of the stomach tends to parallel the arterial supply. The venous efflux ultimately passes through the portal venous system, and this is reflected in the fact that the liver is the primary site for distant metastatic spread.
Фигура 53.1. Кровоснабжение желудка и анатомические взаимосвязи желудка с соседними органами, которые, вероятно, будут вовлечены в прямую экспансию опухоли желудка Т4. а., артерия.
The lymphatic drainage of the stomach is extensive, and distinct anatomic groups of perigastric lymph nodes have been defined according to their relationship to the stomach and its blood supply. There are six perigastric lymph node groups. In the first echelon (stations 1 to 6) are the right and left pericardial nodes (stations 1 and 2). Along the lesser curvature are the lesser curvature nodes (station 3) and the suprapyloric nodes (station 5). Along the greater curvature, the gastroepiploic nodes or greater curvature nodes (station 4), and the subpyloric nodes (station 6). In the second echelon (stations 7 to 12) are the nodes along named arteries, which include the left gastric, common hepatic, celiac, splenic hilum, splenic artery, and hepatoduodenal lymphatics (stations 7 to 12, respectively), which drain into the celiac and periaortic lymphatics. The third echelon (stations 13 to 16) contains the posterior to pancreatic head, superior mesenteric vessels, middle colic artery, and para-aortic lymphatics (stations 13 to 16, respectively). Proximally are the lower esophageal lymph nodes (stations 20 to 22); extensive spread of gastric cancer along the intrathoracic lymph channels may be manifested clinically by a metastatic lymph node in the left supraclavicular fossa (Virchow node) or left axilla (Irish node). Tumor spread to the lymphatics in the hepatoduodenal ligament can extend along the falciform ligament and result in subcutaneous periumbilical tumor deposits (Sister Mary Joseph nodes).
Патология и биология опухоли
Approximately 95% of all gastric cancers are adenocarcinomas. The term gastric cancer refers to adenocarcinoma of the stomach. Other malignant tumors are rare and include squamous cell carcinoma, adenoacanthoma, carcinoid tumors, small-cell carcinoma, mucinous carcinoma, hepatoid adenocarcinoma, oncocytic (parietal gland) carcinoma, sarcomatoid carcinoma, lymphoepithelioma-like carcinoma, adenocarcinoma with rhabdoid features, gastric carcinoma with osteoclast-like giant cells, neuroendocrine tumor, gastrointestinal stromal tumor, or leiomyosarcoma.5 Although no normal lymphoid tissue is found in the gastric mucosa, the stomach is the most common site for lymphomas of the gastrointestinal tract. The increased awareness of association between mucosa-associated lymphoid tissue lymphomas and Helicobacter pylori may explain, in part, the rise in incidence, although the incidence of mucosa-associated lymphoid tissue gastric lymphomas is decreasing likely because of effective treatment against H. pylori.
In terms of pathogenesis, two new concepts are worth mentioning: bone marrow participation in gastric carcinogenesis and gastric cancer stem cells.5 It has been hypothesized that the gastric epithelial cells acquiring abnormal phenotype (resembling intestinal epithelium) originate from gastric stem cells localized to the only cell replication zone of the gastric glands (i.e., the isthmus). However, Houghton et al.6 and Stoicov et al.7 demonstrated in a rodent model of Helicobacter-induced gastric cancer that the entire cancer mass was derived from cells originating in the bone marrow. This interesting phenomenon was observed by other authors studying solid cancers in patients receiving bone marrow transplantation.8 Recent evidence proposes the existence of cancer stem cells or stem-like cancer cells in various cancers. Although controversial, cancer stem cells are defined as cancer cells with the exclusive ability to initiate tumors, metastasize, and self-renew tumors. In gastric cancer, several investigators suggested the existence of gastric cancer stem cells (i.e., CD44+) and side population cells. These cells showed relative resistance to chemotherapy and radiation, and exclusive ability to initiate tumors. These important observations might lead to novel approaches to the diagnosis and treatment of gastric cancer in the next decade.9
Several staging schemas have been proposed based on the morphologic features of gastric tumors. The Borrmann classification divides gastric cancer into five types depending on macroscopic appearance. Type I represents polypoid or fungating cancers, type II encompasses ulcerating lesions surrounded by elevated borders, type III represents ulcerated lesions infiltrating the gastric wall, type IV includes diffusely infiltrating tumors, and type V gastric cancers are unclassifiable cancers. The gross morphologic appearance of gastric cancer and the degree of histologic differentiation are not independent prognostic variables. Ming10 has proposed a histomorphologic staging system that divides gastric cancer into either a prognostically favorable expansive type or a poor prognosis infiltrating type. Based on an analysis of 171 gastric cancers, the expansive-type tumors were uniformly polypoid or superficial on gross appearance, whereas the infiltrative tumors were almost always diffuse. Grossly ulcerated lesions were divided between the expansive or infiltrative forms. Broder classification of gastric cancer grades tumors histologically from 1 (well-differentiated) to 4 (anaplastic). Bearzi and Ranaldi11 have correlated the degree of histologic differentiation with the gross appearance of 41 primary gastric cancers seen on endoscopy. A total of 90% of protruding or superficial cancers were well differentiated (Broder grade 1), whereas almost half of all ulcerated tumors were poorly differentiated or diffusely infiltrating (Broder grades 3 and 4).
The most widely used classification of gastric cancer is by Laurén.12 It divides gastric cancers into either intestinal or diffuse forms. This classification scheme, based on tumor histology, characterizes two varieties of gastric adenocarcinomas that manifest distinctively different pathology, epidemiology, genetics, and etiologies. The intestinal variety represents a differentiated cancer with a tendency to form glands similar to other sites in the gastrointestinal tract, but in particular the colon type, hence the intestinal type. In contrast, the diffuse form exhibits very little cell cohesion with a predilection for extensive submucosal spread and early metastases. Although the diffuse-type cancers are associated with a worse outcome than the intestinal type, this finding is not independent of tumor, node, and metastasis (TNM) stage. The molecular pathogenesis of these two distinct forms of gastric cancer is also different. Although the intestinal type represents H. pylori–initiated multistep progression with less defined progressive genetic alterations, the diffuse type main carcinogenic event is loss of expression of E-cadherin (CDH1 gene). E-cadherin is a molecule involved in cell-to-cell adhesion; loss of its expression leads to noncohesive growth, hence the diffuse type. In tumors that display both intestinal and diffuse phenotypes, the CDH1 mutation and loss of E-cadherin function are observed only within the diffuse phenotype.
Молекулярная классификация рака желудка
Full description of molecular pathogenesis of gastric cancer is beyond the scope of this chapter. However, evidence shows that classification of gastric cancer for purposes of prognosis, treatment, and staging will be based in the future on molecular changes rather than or in addition to the classical histologic features.13,14 Gene expression data from 300 cases has been used to describe four molecular subtypes of gastric cancer: mesenchymal-like type, microsatellite-unstable tumors, tumor protein 53 (TP53)-active, and TP53-inactive types, representing approximately 30%, 22%, 24%, and 23% of samples within the National Cancer Institute’s (NCI’s) Cancer Genome Atlas, respectively. The subtypes are associated with distinct patterns of molecular alterations, disease progression, and prognosis. For instance, the mesenchymal-like type has the worst prognosis, tends to occur at an earlier age, and has the highest frequency of recurrence. Conversely, microsatellite-unstable tumors have the best overall prognosis and the lowest frequency of tumor recurrence. The TP53-active and TP53-inactive types include patients with intermediate prognosis and recurrence rates. Classical Laurén histologic subtypes correlate somewhat with genomic subtypes: Diffuse-type adenocarcinomas are predominant within the mesenchymal-like subtype, whereas intestinal-type adenocarcinomas are the predominant histologic subtype within microsatellite-unstable subtype. This genomic classification has the potential to impact on management; for instance, immunotherapy approaches are likely to be most successful in the hypermutated microsatellite-unstable tumors, whereas human epidermal growth factor receptor 2 (HER2)-targeted agents are likely to be most successful in TP53-inactive types that frequently have overamplified HER2 genes. Such approaches, however, should be considered experimental; it remains to be seen if sequencing-based genomic subtyping is a better therapeutic discriminator than simple HER2, programmed cell death protein 1 (PD-1)/programmed cell death protein ligand 1 (PD-L1), and microsatellite instability (MSI) testing.15
Carcinomas of the stomach can spread by local extension to involve adjacent structures and can develop lymphatic metastases, peritoneal metastases, and distant metastases. These extensions can occur by the local invasive properties of the tumor, lymphatic spread, or hematogenous dissemination. The initial growth of the tumor occurs by penetration into the gastric wall, extension through the wall, within the wall longitudinally, and subsequent involvement of an increasing percentage of the stomach. The two modes of local extension that can have major therapeutic implications are tumor penetration through the gastric serosa, where the risk of tumor invasion of adjacent structures or peritoneal spread is increased, and lymphatic involvement. Zinninger16 in 1954 evaluated spread within the gastric wall and found a wide variation in its extent. Tumor spread is often through the intramural lymphatics or in the subserosal layers. Local extension can also occur into the esophagus or the duodenum. Duodenal extension is rare (0.5% to 1.8% of all resected cases), portrays poor prognosis, and is principally through the muscular layer by direct infiltration and through the subserosal lymphatics but is not generally to any great extent. Extension into the esophagus occurs primarily through the submucosal lymphatics.17,18
Local extension does not occur solely by radial intramural spread but also by deep invasion through the wall to adjacent structures (omentum, spleen, adrenal gland, diaphragm, liver, pancreas, or colon). Many studies report that 60% to 90% of patients had primary tumors penetrating the serosa or invading adjacent organs and that at least 50% had lymphatic metastases. In the largest series reporting on 10,783 patients with gastric cancer from Korea, 57% of the patients had lymph node metastasis, and the average number of involved lymph nodes was five.19,20 Of the 1,577 primary gastric cancer cases admitted to Memorial Sloan Kettering Cancer Center (MSKCC) between 1985 and 1998, 60% of the 1,221 resected cases had evidence of serosal penetration and 68% had positive nodes. Lymph node metastases were found in 18% of pT1 lesions and 60% of pT2 lesions after R0 resection in 941 patients. The highest incidence of lymphatic metastasis was seen in tumors diffusely involving the entire stomach. Tumors located at the gastroesophageal junction also had a high incidence relative to other sites.
The pattern of nodal metastases also varies depending on the location of the primary site. In a study reporting on 1,137 patients with early gastric cancer (EGC), tumors located in the upper, middle, and lower third of the stomach had 12%, 10%, and 8% nodal involvement, respectively. The most common nodal station metastases for the upper, middle, and lower third of the stomach were stations 3 (lesser curvature), 3/4/7 (lesser/greater curvature/left gastric artery), and 3/4/6 (lesser/greater curvature/infrapyloric), respectively.21 Earlier studies that included more advanced gastric cancers showed that the left gastric artery nodes were at increased risk for nodal metastases independent of tumor location.21,22
Gastric cancer recurs in multiple sites, locoregionally and systemically. Patterns of failure are variable. These differences are likely related to the patient cohorts evaluated, the time at which failure was determined, and the method of determination of failure patterns. Recent series from the MSKCC and Korea do shed light on modern patterns of failure.23,24 In the report from MSKCC, recurrence patterns of 1,038 patients who underwent R0 gastrectomy with D2 lymphadenectomy (61%) were analyzed; complete data on recurrence were available in 367 of 496 (74%) patients who experienced recurrence. The locoregional area was involved in 199 (54%) patients. Distant sites were involved in 188 (51%) patients, and peritoneal recurrence was detected in 108 (29%) patients. More than one site of recurrence was detected: distal, peritoneal, and locoregional recurrences in 9 (2.5%); locoregional and peritoneal in 34 (9.3%); locoregional and distant in 61 (16.6%); and distant and peritoneal in 15 (4.1%) patients. On multivariate analysis, peritoneal recurrence was associated with female gender, advanced T stage, and distal- and diffuse-type tumors; locoregional recurrence was associated with proximal location, early T stage, and intestinal-type tumors. In the study from Korea, recurrence patterns were analyzed in 2,038 patients who were treated with potentially curative gastrectomy.24 Of 508 patients who developed recurrence, 33% involved locoregional sites, 44% were peritoneal, and 38% were distant. At time of presentation, 35% of patients presented with distant metastasis, with 4% to 14% having liver metastases.
Клиническая картина и оценка до лечения
Признаки и симптомы
Because of the vague, nonspecific symptoms that characterize gastric cancer, many patients are diagnosed with advanced-stage disease. Patients may have a combination of signs and symptoms such as weight loss (22% to 61%); anorexia (5% to 40%); fatigue, epigastric discomfort, or pain (62% to 91%); and postprandial fullness, heart burn, indigestion, nausea, and vomiting (6% to 40%). None of these unequivocally indicates gastric cancer. In addition, patients may be asymptomatic (4% to 17%). Weight loss and abdominal pain are the most common presenting symptoms at initial encounter. Weight loss is a common symptom, and its clinical significance should not be underestimated. Dewys et al.25 found that in 179 patients with advanced gastric cancer, >80% of patients had a >10% decrease in body weight before diagnosis. Furthermore, patients with weight loss had a significantly shorter survival than did those without weight loss.26
In some patients, symptoms may suggest the presence of a lesion at a specific location. Up to 25% of the patients have history/symptoms of peptic ulcer disease. A history of dysphagia or pseudoachalasia may indicate the presence of a tumor in the cardia with extension through the gastroesophageal junction. Early satiety is an infrequent symptom of gastric cancer but is indicative of a diffusely infiltrative tumor that has resulted in loss of distensibility of the gastric wall. Delayed satiety and vomiting may indicate pyloric involvement. Significant gastrointestinal bleeding is uncommon with gastric cancer; however, hematemesis does occur in approximately 10% to 15% of patients, and anemia in 1% to 12% of patients. Signs and symptoms at presentation are often related to spread of disease. Ascites, jaundice, or a palpable mass indicate incurable disease. The transverse colon is a potential site of malignant fistulization and obstruction from a gastric primary tumor. Diffuse peritoneal spread of disease frequently produces other sites of intestinal obstruction. A large ovarian mass (Krukenberg tumor) or a large peritoneal implant in the pelvis (Blumer shelf), which can produce symptoms of rectal obstruction, may be palpable on pelvic or rectal examination. Nodular metastases in the subcutaneous tissue around the umbilicus (Sister Mary Joseph node) or in peripheral lymph nodes such as in the supraclavicular area (Virchow node) or axillary region (Irish node) represent areas in which a tissue diagnosis can be established with minimal morbidity. There is no symptom complex that occurs early in the evolution of gastric cancer that can identify individuals for further diagnostic measures. However, alarming symptoms (dysphagia, weight loss, and palpable abdominal mass) are independently associated with survival; increased number and the specific symptom is associated with mortality.
Список факторов риска, ассоциированных с раком желудка, представлен в таблице 53.1. These factors might be use for risk stratification in screening programs. Mass screening programs for gastric cancer have been most successful in high-risk areas, especially in Japan. A variety of screening tests have been studied in Japanese patients, with a sensitivity and specificity of approximately 90%.Gastric cancer screening modalities include endoscopy (upper endoscopy), radiology (contrast radiography), and serology (serum trefoil factor 3, microRNAs, and multianalytes blood tests). Screening typically includes serology for H. pylori, the use of double-contrast barium radiographs, or upper endoscopy with risk stratification (OLGA staging system for gastric cancer risk).
Таблица 53.1. Факторы, ассоциированные с высоким риском развития рака желудка
- Высокое потребление соли
- Высокое потребление нитратов
- Низкое содержание витаминов А и С в пище
- Некачественное приготовление пищи (копченое, пересоленное)
- Недостаточное охлаждение
- Загрязненная питьевая вода (колодезная вода)
- Производство резины
- Переработка угля
- Курение сигарет
- Инфекция Helicobacter pylori
- Вирус Эпштейна-Барр
- Радиационное облучение
- Перенесенные ранее операции на желудке по поводу доброкачественной язвенной болезни желудка
- Предшествующее лечение мукоза-ассоциированной лимфоидной лимфомы
- Группа крови А
- Пернициозная анемия
- Семейная история без известных генетических факторов (родственник первой степени с раком желудка)
- Наследственный диффузный рак желудка (CDH1 мутация)
- Семейный рак желудка
- Наследственный неполипозный рак толстого кишечника
- Семейный аденоматозный полипоз
- Синдром Ли-Фраумени
- BRCA1 и BRAC2
- Прекурсорные поражения
- Аденоматозные полипы желудка
- Хронический атрофический гастрит
- Интестинальная метаплазия
- Болезнь Менетрие
- Этнос (in the United States, gastric cancer is more common among Asian/Pacific Islanders, Hispanics, and African Americans)
- Ожирение (сила этой связи не ясна)
Ohata et al.33 reported on 4,655 asymptomatic patients at an average age of 50 years old who were followed for 7.7 years. Atrophic gastritis was identified using pepsinogen and H. pylori testing: 2,341 (52%) were H. pylori– positive with nonatrophic gastritis, 967 (21%) were H. pylori–negative without atrophic gastritis, 1,316 (28%) were H. pylori–positive with atrophic gastritis, and 31 (0.7%) had severe atrophic gastritis. The rates of gastric cancer development per population per year were 107/100,000 for H. pylori–positive with nonatrophic gastritis, 0/100,000 for H. pylori–negative without atrophic gastritis, 238/100,000 for H. pylori–positive with atrophic gastritis, and 871/100,000 for severe atrophic gastritis. Thus, the number of endoscopies needed to detect one cancer was 1/1,000, 0/1,000, 1/410, and 1/114, respectively. Similar data were reported on 6,985 patients by Watabe et al.34 Surveillance in endemic populations is clinically important because EGC has a very high cure rate with surgical treatment. However, the fact that gastric cancer remains one of the top causes of death in Japan indicates the limitations of a mass-screening program when the entire population at risk is not effectively screened. However, more recent studies indicate that for surveillance programs to be effective and feasible from an economical perspective, they should be instituted only in high-risk populations (>20/100,000 incidence of disease) and include the following components: detection and eradication of H. pylori, serum pepsinogen (pepsinogen I/II ratio), endoscopy with biopsy, and risk stratification before and after H. pylori eradication using a system such as the OLGA staging system for gastric cancer risk. Such programs are expected to avoid long-term repeated screening of approximately 70% of the population who are at low risk of developing gastric cancer. A U.S. study found that screening and eradication of H. pylori in Japanese Americans is cost-effective in preventing gastric cancer.35 These findings were confirmed by two studies from the United Kingdom.36,37
Fluorodeoxyglucose (FDG) positron emission tomography (PET) and PET/computed tomography (CT) scans are being evaluated in Japan as a potentially useful modality for the purpose of gastric cancer screening. A recently published trial from the National Center for Global Health and Medicine in Tokyo studied over 150,000 asymptomatic patients as part of FDG-PET screening. With a sensitivity and positive predictive value of 38% and 34%, respectively, the authors appropriately concluded that gastric endoscopy should be included as part of screening programs in order to increase rate of gastric cancer detection.38
Most gastric cancers have at least one elevated tumor marker, but some benign gastric diseases show elevated serum tumor markers as well. Tumor markers in gastric cancer continue to have limited diagnostic usefulness, with their role more informative in follow-up after primary treatment. The most commonly used markers are serum carcinoembryonic antigen (CEA), cancer antigen (CA) 19-9, CA 50, and CA 72-4. There is wide variation in the reported serum levels of these markers; positive CEA and CA 19-9 levels varied from 8% to 58% and 4% to 65%, respectively. Overall, the sensitivity of each serum tumor marker alone as a diagnostic marker of gastric cancer is low. However, when the levels are elevated, it does usually correlate with stage of disease. Combining CEA with other markers, such as CA 19-9, CA 72-4, or CA 50, can increase sensitivity compared with CEA alone.
In a large study evaluating serum CEA, α-fetoprotein, human chorionic gonadotropin β, CA 19-9, CA 125, as well as tissue staining for HER2 in gastric cancer patients, only human chorionic gonadotropin β level >4 IU/L and a CA 125 level ≥350 U/mL had prognostic significance. Elevated serum tumor marker levels in gastric cancer before chemotherapy may reflect not only tumor burden but also biology of disease.
Endoscopy is the best method to diagnose gastric cancer as it visualizes the gastric mucosa and allows biopsy for a histologic diagnosis. Chromoendoscopy helps identify mucosal abnormalities through topical mucosal stains. Magnification endoscopy is used to magnify standard endoscopic fields by 1.5- to 150-fold. Narrow band imaging affords enhanced visualization of the mucosal microvasculature. Confocal laser endomicroscopy permits in vivo, three-dimensional microscopy including subsurface structures with diagnostic accuracy, sensitivity, and specificity of 97%, 90%, and 99.5%, respectively.41
Endoscopic ultrasound (EUS) is a tool for preoperative staging and selection for neoadjuvant therapy. It is used to assess the T and N stage of primary tumors. A study of 225 patients from MSKCC found that the concordance between EUS and pathology was lower than expected. The accuracy for individual T and N stage were 57% and 50%, respectively. However, the combined assessment of N stage and serosal invasion identified 77% of the patients at risk of disease-related death after curative resection.42 Other investigators compared the accuracy of EUS with that of multidetector computed tomography (MDCT) and magnetic resonance imaging (MRI) and found that the overall accuracy was 65% to 92% (EUS), 77% to 89% (MDCT), and 71% to 83% (MRI) for T stage and 55% to 66% (EUS), 32% to 77% (MDCT), and 54% to 87% (MRI) for N stage, respectively. The corresponding sensitivity and specificity for serosal involvement were 78% to 100% (EUS), 83% to 100% (MDCT), and 89% to 93% (MRI) for T stage, and 68% to 100% (EUS), 80% to 97% (MDCT), and 91% to 100% (MRI) for N stage, respectively.41
Once gastric cancer is suspected, a triphasic CT with oral and intravenous contrast of the abdomen, chest, and pelvis is imperative. These patients should be discussed in a multidisciplinary setting. In a study of 790 patients who underwent MDCT prior to surgery, the overall accuracy in determining T stage was 74% (T1 46%, T2 53%, T3 86%, and T4 86%), and for N staging, it was 75% (N0 76%, N1 69%, and N2 80%).43 The sensitivity, specificity, and accuracy for lymph node metastasis were 86%, 76%, and 82%, respectively.43 MDCT with thin- sliced multiplanar reconstruction (MPR) and water filling is increasingly used. The accuracy rate for advanced gastric cancer was 96% and for EGC, it was 41%. An improvement on axial CT and MPR-MDCT was the addition of staging with three-dimensional MPR-MDCT. The detection rate for MPR with virtual gastroscopy was 98%. MPR-MDCT with combined water and air distention is superior to conventional axial imaging.
МРТ не используется рутинно в дооперационной стадийности рака желудка. Несколько исследований показали, что КТ и МРТ сопоставимы с точки зрения точности и понимания. Тем не менее, МРТ является полезным методом для дальнейшей характеристики поражений печени, выявленных в ходе предоперационной КТ.
Whole-body FDG-PET is being applied increasingly in the evaluation of gastrointestinal malignancies.38 In gastric cancer, approximately half of the primary tumors are FDG-negative; the diffuse (signet cell) subtype was most likely to be non-FDG avid, likely because of decreased expression of the glucose transporter 1 (GLUT1). In patients with non-FDG–avid primary tumor, FDG-PET/CT is not useful. PET/CT was tested as a tool to predict response to neoadjuvant chemotherapy. Ott et al.46 reported 90% 2-year survival in patients with PET-defined response (<35% decrease standardized uptake value [SUV]) versus 25% for patients not responding to PET. PET response could be detected as early as 14 days. At least 60% of the patients were PET-nonresponding patients and thus could have been spared further chemotherapy. Authors of the MUNICON trial reported on patients who were PET nonresponders by day 14 after cisplatin and fluorouracil (5-FU) (CF) neoadjuvant chemotherapy, and subsequently were sent for surgery, and patients who were PET responders and continued 3 months of neoadjuvant therapy before surgery. The PET-responding patients had a survival benefit (hazard ratio [HR], 2.13; P < .15). In PET-nonresponding patients, stopping the chemotherapy did not affect long-term survival. Recent studies, including one large meta-analysis, showed that in terms of diagnostic accuracy and lymph node staging, EUS, MDCT, MRI, and PET/CT are comparable modalities. There were no significant differences between mean sensitivities and specificities.47,48 Even in patients whose tumors were FDG avid, FDG-PET/CT scans did not identify occult peritoneal disease (0 of 18) but did identify extraperitoneal M1 disease in 9 patients with bone (n = 2), liver (n = 4), and retroperitoneal lymph node (n = 3) involvement. In patients with FDG-avid tumors, PET may be useful in detecting metastatic disease and follow-up for recurrence. Interestingly, the presence of GLUT1– and FDG-avid gastric cancers may be associated with decreased OS. The role of PET/CT in the primary staging of gastric cancer remains to be established; its role might be better defined in advanced disease.49–53
In a prospective study of 113 patients who were clinically staged as locally advanced but nonmetastatic gastric cancer (T3 to T4, Nx or N+, M0), investigators found that FDG-PET/CT did identify occult metastatic disease in about 10% of patients. In this study, FDG-PET/CT did not identify occult peritoneal disease, suggesting a necessary role for laparoscopy in preoperative staging of locally advanced gastric cancer.54 A cost evaluation was also performed, and it suggested that if FDG-PET/CT is included as part of the staging algorithm, that would result in an estimated cost savings of approximately $13,000 U.S. dollars per patient.55
Этапная лапароскопия и перитонеальная цитология
Этапная лапароскопия с перитонеальным лаважем должна быть неотъемлемой частью долечебной стадийной оценки пациентов, предположительно имеющих локализованный рак желудка. Современные неинвазивные методы, используемые в предоперационной стадийности рака желудка, имеют чувствительность значительно <100%, особенно в случаях малого объема перитонеального карциноматоза. Современные методы КТ не могут последовательно идентифицировать метастазы макроскопически малого объема размером менее 5 мм. Лапароскопически прямо обследуют брюшную и висцеральную поверхности на предмет выявления КТ-оккультных метастазов небольшого объема. Стадийная лапароскопия также позволяет оценить перитонеальную цитологию и лапароскопическое УЗИ. Лапароскопическая стадия проводится для избавления от нелечебных операций и для потенциальной стратификации в различных исследованиях. 56–58
The rate of detection of CT-occult M1 disease by laparoscopy depends on the quality of CT scanning and interpretation. Muntean et al.59 reported on 98 patients with primary gastric cancer: 45 underwent staging laparoscopy with subsequent surgery and 53 went directly to surgery. An unnecessary laparotomy was avoided in 38% of the patients. The overall sensitivity and specificity were 89% and 100%, respectively. Nonetheless, even high quality MDCT is insufficiently sensitive for detection of low-volume extragastric disease and thus CT, EUS, and laparoscopy are complementary staging studies.
The value of peritoneal cytology as a preoperative staging tool in patients with gastric cancer who are potential candidates for curative resection by EUS and CT has been examined by several investigators.60,61 Bentrem et al.62 reported on 371 patients who underwent R0 resection, 6.5% of whom had positive cytology after staging laparoscopy. Median survival of patients with positive cytology was 14.8 versus 98.5 months for patients with negative cytology findings (P < .001). Positive cytology predicted death from gastric cancer (relative risk, 2.7; P <.001) and is tantamount to M1 disease. Several groups confirmed these findings and concluded that staging laparoscopy with peritoneal cytology can change the management of gastric cancer in 6.5% to 52% of patients.63,64–67
Laparoscopy can be performed as a separate staging procedure prior to definitive treatment planning or immediately prior to planned laparotomy for gastrectomy. When performed as a separate procedure, laparoscopy has the disadvantage of the additional risks and expense of a second general anesthetic. However, separate procedure laparoscopy allows the additional staging information including cytology acquired at laparoscopy to be reviewed and discussed with the patient and in multidisciplinary treatment group prior to definitive treatment planning. Laparoscopic ultrasound (LUS) and “extended laparoscopy” are techniques that may increase the diagnostic yield of laparoscopy. Preliminary results reveal conflicting data on the added benefit of LUS and extended laparoscopy. Further prospective studies will be required to evaluate the cost-benefit relationship of LUS and extended laparoscopy in the routine or selective workup of patients with gastric cancer.
Although laparoscopic staging is thought to detect CT-occult metastatic disease in approximately 40% of patients and spares nontherapeutic operations in approximately one-third of patients with gastric cancer, one needs to remember that tumor biology, not staging, will eventually guide outcomes. For advanced gastric cancer staging, laparoscopy improves decision making.68 Clearly, not all patients benefit from preoperative laparoscopic staging; therefore, future studies should address the issue of selective laparoscopy based on noninvasive staging (i.e., patients with T1 tumors). Staging laparoscopy with or without cytology should be considered only if therapy will be altered consequent to information obtained by laparoscopy.
Стадийность, классификация и прогноз
For patients with surgically treated gastric adenocarcinoma, both pathologic staging (American Joint Committee on Cancer [AJCC]/International Union Against Cancer [UICC] or Japanese system) and classification of the completeness of resection (R classification) should be done. Additionally, the AJCC recommends collection of additional prognostic factors: tumor location, serum CEA and CA 19-9 (both are not independent prognostic factors [IDPFs], used for monitoring), HER2 (not an IDPF if HER2-positive tumor), MSI (MSI-high [MSI-H] better prognosis, PD-1 therapy), molecular markers (Epstein-Barr virus [EBV], MSI, copy number, epithelial– mesenchymal transition [EMT]), and histopathologic grade and type. The pathologic reports should include AJCC eighth edition staging, tumor location, size and penetration, histologic classification, nodal involvement and number, lymphovascular invasion (LVI) status, D1 versus D2 by station, margin status, number of metastatic sites and location, and Eastern Cooperative Oncology Group (ECOG). Initial management is dependent on meticulous clinical staging.69–71
American Joint Committee on Cancer/International Union Against Cancer Tumor, Node, Metastasis Staging
The AJCC/UICC TNM staging system, eighth edition, for gastric cancer is outlined in Table 53.2.69,72–74 The AJCC/UICC stage-stratified survival rates based on the following: clinical stage all-comers in the National Cancer Database (NCDB) (2004 to 2008; n = 7,306; follow-up = 12 years); clinical stage database of patients receiving curative or palliative resection at the Shizuoka Cancer Center (2002 to 2015; n = 4,091; follow-up = 47 months); International Gastric Cancer Association (IGCA) data on pathologic stage of patients undergoing surgical resection and adequate lymphadenectomy (D2) without prior chemotherapy or radiation (2000 to 2004; follow-up = 5 years; n = 25,411); and patients from the NCDB (2004 to 2008; n = 683; follow-up = 23 months) who received neoadjuvant therapy (stage ypTNM; Table 53.3). Changes to note in the eighth edition of the AJCC/UICC staging system include the following: anatomic considerations—EGJ tumors with epicenter <2 cm and >2 cm into the proximal stomach are considered EGJ and gastric cancers, respectively; cardia cancers not involving the EGJ are considered gastric cancer; lymph nodes—N3 was subdivided into N3a and N3b; prognostic stage grouping—cTNM differ from pTNM, ypTNM are the same as pTNM, and T4aN2 and T4bN0 are classified as stage IIIA.73,75
|Первичная опухоль (T)|
|TX||Первичная опухоль не может быть оценена|
|T0||Нет свидетельства первичной опухоли|
|Tis||Карцинома in situ: интраэпителиальная опухоль без инвазии в собственную пластинку (lamina propria), высокозлокачественная дисплазия|
|T1a||Опухоль инвазирует собственную пластинку или мышечную оболочку слизистой (muscularis mucosae)|
|T1b||Опухоль инвазирует подслизистую (submucosa)|
|T2||Опухоль инвазирует мышечную пластинку (muscularis propria)|
|T3||Опухоль проникает через субсерозную соединительную ткань без инвазии в висцеральную брюшину или прилегающие структуры|
|T4a||Опухоль инвазирует в серозную оболочку (висцеральную брюшину)|
|T4b||Опухоль инвазирует в прилегающие структуры/органы|
|Региональные лимфатические узлы (N)|
|NX||Региональные лимфатические узлы не могут быть оценены|
|N0||Нет метастазов в региональные лимфоузлы|
|N1||Метастазы в 1-2 региональных лимфатических узла|
|N2||Метастазы в 3-6 региональных лимфатических узлов|
|N3a||Метастазы в 7-15 региональных лимфатических узлов|
|N3b||Метастазы в 16 или более региональных лимфатических узлов|
|Отдаленный метастаз (M)|
|M0||Нет отдаленных метастазов|
|Анатомическая стадия/ прогностические группы||5-летняя общая выживаемость|
|T4a||N1 или N2||M0|
|Stage IIIB||T4b||N1 или N2||M0|
|Stage IIIC||T4b||N3a или||M0|
|Stage IV||Любой T||Любой N||M1||5.0%|
Таблица 53.3. Стадийная система японской ассоциации рака желудка (Japanese Gastric Cancer Association Staging System)
|T1||Инвазия опухоли в mucosa и/или muscularis mucosa или submucosa|
|T2||Инвазия опухоли в muscularis propria или subserosa|
|T3||Пенетрация опухолью серозной оболочки|
|T4||Инвазия опухоли в прилегающие структуры|
|N0||Нет свидетельства метастазирования в лимфатический узел|
|N1||Метастазирование в лимфоузлы 1 группы, но без метастазирования в лимфоузлы 2–3 групп|
|N2||Метастазирование в лимфоузлы 2 группы, но без метастазирования в лимфоузлы 3 группы|
|N3||Метастазирование в лимфатические узлы 3 группы|
|Стадия метастазирования в печень (H)|
|H0||Нет метастазов в печень|
|H1||Метастазирование в печень|
|Стадия перитониального метастазирования (P)|
|P0||Нет перитонеального метастазирования|
|Перитонеальная цитологическая стадия (CY)|
|CY0||Доброкачественные/неопределенные клетки в перитонеальной цитологии а|
|CY1||Раковые клетки в перитонеальной цитологии|
|CYX||Перитонеальная цитология не проводилась|
|Другие отдаленные метастазы (М)|
|M0||Нет отдаленных метастазов (хотя могут присутствовать перитонеальные, печеночные или цитологические метастазы)|
|M1||Отдаленные метастазы, кроме метастазов в брюшину, печень или цитологические|
|Группировка по стадиям|
|H1, P1, CY1, M1|
a Cytology believed to be “suspicious for malignancy” should be classified as CY0.
Фигура 53.2. Definition of American Joint Committee on Cancer/International Union Against Cancer T stage based on depth of penetration of the gastric wall.
In the AJCC/UICC staging system, tumor (T) stage is determined by depth of tumor invasion into the gastric wall and extension into adjacent structures (Fig. 53.2). The relationship between T stage, the overall stage, and survival is well defined (Fig. 53.3). Nodal stage (N) is based on the number of involved lymph nodes, a criterion that may predict outcome more accurately than the location of involved lymph nodes. Tumors with 1 to 2 involved nodes are classified as pN1, 3 to 6 involved nodes are classified as pN2, and those with 7 or more involved nodes are classified as pN3 (N3a has 7 to 15 nodes and N3b has ≥16 nodes). The use of numerical thresholds for nodal classification has gained increasing acceptance, although the extent of lymphadenectomy and rigor of pathologic assessment may affect results. The nodal numerical threshold approach is based on observations that survival decreases as the number of metastatic lymph nodes increases and that survival significantly decreases at three or more involved76 lymph nodes and again at seven or more involved lymph nodes.
Фигура 53.3. Disease-specific survival by American Joint Committee on Cancer stage grouping. Numbers beneath x-axis indicate patients at risk.
Given the reliance on numerical thresholds for nodal staging, it is extremely important that adequate number of lymph nodes are retrieved surgically and examined pathologically (at least 15 and preferably 30). However, recent reports document poor compliance with AJCC staging primarily because the number of lymph nodes removed and/or examined (≤15) was insufficient. Positive peritoneal cytology is classified as M1. Ratio-based lymph node classification (number of positive nodes over number of total nodes resected and evaluated) is an alternative to the threshold-based system currently utilized by the AJCC/UICC staging systems. It may minimize the confounding effects of regional variations in the extent of lymphadenectomy and pathologic evaluation on lymph node staging and thereby reduce stage migration. Sun et al.77 evaluated the ratio between metastatic and examined lymph nodes (RML) in a group of 2,159 patients who underwent curative gastrectomy. The anatomic location, number of positive lymph nodes (AJCC/UICC), and RML were analyzed for staging accuracy and relationship to survival. RML was an independent prognostic factor for survival and reduced stage migration. These findings were confirmed by several investigators reporting on approximately 2,000 patients treated by R0 gastrectomy.78–83
Японская стадийная система
The most recent Japanese Classification for Gastric Carcinoma was published in 1998.84 The Japanese classification and staging system is more detailed than the AJCC/UICC staging system and places more emphasis on the distinction between clinical, surgical, pathologic, and “final” staging (prefixes “c,” “s,” “p,” and “f,” respectively). For example, a surgically treated and staged patient with locally advanced, nonmetastatic gastric cancer might be staged as pT3, pN2, sH0, sM0, stage f-IIIB (where H0 denotes no hepatic metastases and the “f” prefix denotes final clinicopathologic stage). The Japanese classification system also includes a classification system for EGC (Fig. 53.4).85
In the combined superficial types, the type occupying the largest area should be described first, followed by the next type (e.g., IIc + III). Type 0I and type 0IIa are distinguished as follows: type 0I, the lesion has a thickness of more than twice that of the normal mucosa; type 0IIa, the lesion has a thickness up to twice that of the normal mucosa.
Similar to the AJCC/UICC staging system, primary tumor (T) stage in the Japanese system is based on the depth of invasion and extension to adjacent structures, as outlined in Table 53.4. However, the assignment of lymph node (N) stage involves much more rigorous pathologic assessment than is required for AJCC/UICC staging. The Japanese system extensively classifies 18 lymph node regions into four N categories (N0 to N3) depending on their relationship to the primary tumor and anatomic location. Most perigastric lymph nodes (nodal stations 1 to 6) are considered group N1. Lymph nodes situated along the proximal left gastric artery (station 7), common hepatic artery (station 8), celiac axis (station 9), splenic artery (station 11), and proper hepatic artery (station 12) are defined as group N2. Para-aortic lymph nodes (station 16) are defined as group N3. However, some lymph nodes, even perigastric nodes for specific tumor locations, can be regarded as M1 disease (i.e., involvement of station 2 in the case of antral tumors). This is because their involvement in antral tumors is rare and portrays a poor prognosis.
Фигура 53.4. Японская классификационная система для раннего рака желудка.
The Japanese staging system also includes elements not included in the AJCC/UICC system (see Table 53.3). These are macroscopic descriptions of the tumor (EGC subtype or Borrmann type for more advanced tumors), extent of peritoneal metastases (classified as P0 to P1), extent of hepatic metastases (H0 to H1), and peritoneal cytology findings (CY0 to CY1). Recent comparison of the Japanese and AJCC/UICC staging systems in 731 patients suggests that both are comparable. However, older studies suggest that the AJCC/UICC system more accurately estimates prognosis.86
Классификация рака пищеводно-желудочного перехода
EGJ cancers (i.e., tumors with a definitive component involving the EGJ) are no longer classified by the AJCC as gastric cancers per se. They are briefly reviewed here for historical reasons. Siewert and Stein87 classified adenocarcinomas of the EGJ (Siewert classification) into three distinct clinical entities that arise within 5 cm of the EGJ: type I arises in the distal esophagus and may infiltrate the EGJ from above, type II arises in the cardia or the EGJ, and type III arises in the subcardial stomach and may infiltrate the EGJ from below. The assignment of tumors to one of these subtypes is based on morphology and the anatomic location of the epicenter of the tumor. The Siewert classification has important therapeutic implications. The lymphatic drainage routes differ for type I versus types II and III lesions. The lymphatic pathways from the lower esophagus pass both cephalad and caudad. In contrast, the lymphatic drainage from the cardia and subcardial regions is caudad. Thus, the Siewert classification provides a practical means for choosing among surgical options. For type I tumors, esophagectomy is required, whereas types II and III tumors can be treated by transabdominal gastrectomy.88,89
The R classification system indicates the amount of residual disease left after tumor resection. R0 indicates no gross or microscopic residual disease, R1 indicates microscopic residual disease (positive margins), and R2 signifies gross residual disease. The R classification has implications for individual patient care and clinical research. Results of clinical trials that include surgery should include information on R status. Readers should be aware of the dual use of the “R” terminology in the gastric cancer literature. Prior to 1995, the Japanese staging and treatment vernacular included an “R level,” which described the extent of lymphadenectomy. The latter is now classified by “D” (for dissection) level.
Номограммы рака желудка: предсказывание индивидуального прогноза пациента после потенциально курабельной резекции
Kattan et al.90 developed a nomogram for predicting individual patient 5-year disease-specific survival using established prognostic factors derived from a population of 1,039 patients with gastric cancer treated by R0 surgical resection without neoadjuvant therapy at a single institution (firstname.lastname@example.org). Clinicopathologic factors incorporated in the nomogram include age and gender, primary tumor site, Laurén classification, numbers of positive and negative lymph nodes resected, and depth of invasion. This nomogram was subsequently validated by several authors. Peeters et al.91 found that the nomogram prognosticates better than the AJCC staging system. Novotny et al.92 validated the nomogram in 862 patients from Germany and the Netherlands; Strong et al.93 compared outcomes using the nomogram in 711 patients from the United States and 1,646 patients from Korea. This tool may be useful for individual patient counseling regarding the use of adjuvant therapy, follow-up scheduling, and clinical trial eligibility assessment and is available for personal handheld computer devices at www.nomograms.org.
Таблица 53.4. Prospective Randomized Trials Comparing D1 versus D2 and D3 Resection for Potentially Curable Gastric Carcinoma
|Study (Ref.)||Extent of lymphadenectomy|
|Groote Schuur Hospital, Cape Town, 1988|
|Number of patients||22||21||—|
|Length of operation (h)||1.7 ± 0.6||2.33 ± 0.7||<.005|
|Postoperative stay (d)||9.3 ± 4.7||13.9 ± 9.7||<.05|
|5-y overall survival (log-rank test)||0.69||0.67||NS|
|Prince of Wales Hospital, Hong Kong, 1994|
|Number of patients||25||29||—|
|Length of operation (h)||140||260||<.05|
|Operative blood loss (mL)||300||600||<.05|
|Median survival (d)||1,511||922||<.05|
|Medical Research Council Trial, United Kingdom, 1999|
|Number of patients||200||200||—|
|Operative mortality (%)||6.5||13||<.04|
|Postoperative complications (%)||28||46||<.001|
|5-y overall survival (%)||35||3||NS|
|Dutch Gastric Cancer Trial, The Netherlands, 1999 (2009, 15-y F/U update)|
|Number of patients||380||331||—|
|Operative mortality rate (%)||4||10||.004|
|Postoperative complications (%)||25||43||<.001|
|Postoperative stay (d)||18||25||<.001|
|5-y overall survival (%)||45||47||NS|
|11-y F/U overall survival (%)||30||35||.53|
|11-y F/U survival (perioperative death excluded)||32||39||.10|
|15-y F/U overall survival||21||29||.34|
|15-y F/U gastric cancer–specific death||48||37||.01|
|Italian Gastric Cancer Study Group, 2004123|
|Number of patients||76||86||—|
|Operative mortality rate (%)||1.3||0||NS|
|Postoperative complication (%)||10.5||16.3||.29|
|Postoperative stay (d)||12||12||NS|
|5-y overall survival||NS||NS||NS|
|Yang-Ming University, Taiwan, 2006126|
|Number of patients||110||111, D3||—|
|Operative mortality rate (%)||0||0||—|
|Postoperative complication (%)||10.1||17.1||.012|
|Postoperative stay (d)||15||19.6||.001|
|5-y overall survival||53.6||59.5||.041|
NS, not stated; F/U, follow-up.
Recently, a large retrospective cohort study of 1,273 patients who underwent resection revealed that having a positive family history of gastric cancer (defined as a self-reported history of cancer in first-degree relatives) was associated with significant reduction in disease-free survival (DFS; P = .012), relapse-free survival (P = .006), and OS (P = .005) when compared with those who did not have a family history of gastric cancer. The improvement in outcomes was more pronounced among patients with stage III or IV gastric cancer, with significant adjusted HRs for DFS (HR, 0.49; 95% confidence interval [CI], 0.29 to 0.84), relapse-free survival (HR, 0.47; 95% CI, 0.30 to 0.87), and OS (HR, 0.47; 95% CI, 0.26 to 0.84), respectively.94–98
Лечение локализованного заболевания
Стадия I заболевания (ранний рак желудка)
Классификация раннего рака желудка и риск нодальных метастазов
EGC has been usefully subclassified by the Japanese Research Society for Gastric Cancer based on endoscopic criteria. The current classification system is used for both in situ and invasive tumors and categorizes tumors based on endoscopic findings as follows: protruded, type 0I; superficial elevated, type 0IIa; flat, type 0IIb; superficial depressed, type 0IIc; and excavated, type 0III (see Fig. 53.4). The English language version of the Japanese EGC classification contains excellent color photos of these subtypes. This classification system is important in describing patients treated by newer endoscopic gastric-sparing resection (ER) for EGC, such as endoscopic mucosal resection (EMR) or endoscopic submucosal dissection (ESD).99,100 The risk for lymph node metastasis is important when evaluating treatment options for patients with EGC. The frequency and anatomic distribution of nodal disease are related to the depth of tumor invasion. In a Japanese series of >5,000 patients who underwent gastrectomy with lymph node dissection for EGC, none of the 1,230 patients with well- differentiated intramucosal tumors <3 cm in diameter (regardless of ulceration) had lymph node metastases.101 None of the 929 patients with EGC without ulceration had nodal metastases, irrespective of tumor size. In contrast, in the subset of >2,000 patients with tumors that invaded the submucosa, the frequencies of lymph node involvement for tumors ≤1.0 cm, 1.1 to 2.0 cm, 2.1 to 3.0 cm, and >3.0 cm were 7.9%, 13.3%, 15.6%, and 23.3%, respectively. Thus, once tumors penetrate into the submucosa, the risk for nodal metastasis increases with tumor size. The estimates of the frequency of nodal disease in EGC are based on conventional light-microscopic histologic assessment. However, the use of more sensitive techniques such as serial sectioning of individual lymph nodes, immunohistochemistry, or reverse transcriptase polymerase chain reaction may increase the frequency of detection of occult micrometastatic disease.109 The clinical significance of micrometastasis remains unknown.
Эндоскопическая резекция слизистой и эндоскопическая диссекция подслизистой оболочки
The English language version of the Japanese EGC classification contains excellent color photos of these subtypes. This classification system is important in describing patients treated by newer ER for EGC, such as EMR or ESD.100 The risk for lymph node metastasis is important when evaluating treatment options for patients with EGC. The frequency and anatomic distribution of nodal disease are related to the depth of tumor invasion (Table 53.5).
A more recent review by Wang et al.110 performed a meta- analysis of six studies comparing ER (n = 618) or surgery (n = 848) for resection of EGC. They showed no difference in OS between ER and gastrectomy with shorter hospital stay and reduced perioperative morbidity in patients undergoing ER.110 There were two studies comparing EMR to surgery, three studies comparing ESD to surgery, and one study comparing both methods to surgery. Five studies were from Asian countries and one from the West. Most common complications associated with ER were bleeding (4.3%) and perforation (5.3%).
There are emerging variations of ER techniques, including the cap suction and cut versus a ligating device. As outcome studies accumulate demonstrating favorable survival, ER is emerging as the definitive management of selected EGCs and is not just reserved for patients in whom gastrectomy cannot be considered. However, randomized controlled trials (RCTs) are needed to establish an outcome advantage over open surgery.111
Ограниченная хирургическая резекция
Given the low rate of nodal involvement for patients with EGC, limited resection may be a reasonable alternative to gastrectomy for some patients. There are no well-accepted pretreatment criteria for selection of patients for limited resection. Based on available pathology studies, patients with small (<3 cm) intramucosal tumors and those with nonulcerated intramucosal tumors of any size may be candidates for ER or limited resection. Surgical options for these patients may include gastrotomy with local excision. This procedure should be performed with full-thickness mural excision (to allow accurate pathologic assessment of T status) and is often aided by intraoperative gastroscopy for tumor localization. Formal lymph node dissection is not required in these patients.
Gastrectomy with D1 lymph node dissection should be considered for patients with EGC who cannot be treated with ER or limited surgical resection, and/or patients who have EGC not included in the extended criteria for ER and/or in Western countries where the ability to perform safe and effective EMR or ESD is limited to very few specialized centers. Gastrectomy with D1 lymph node dissection allows for adequate pathologic staging and local therapy for these patients at increased risk of nodal metastasis. Dissection of level I (stations 2 to 6) lymph nodes is a reasonable minimum standard at this time for higher risk EGCs. The roles for nodal “sampling” without formal node dissection (D0 dissection) and sentinel lymph node (SLN) mapping and biopsy in the treatment of EGC remain undefined at this time.
Стадия II и стадия III заболевания
Surgical resection of the primary tumor and regional lymph nodes is the cornerstone of treatment for patients with localized gastric cancer. However, for stage II and III disease, surgery is necessary but often not sufficient for cure. The general therapeutic goals are (1) to achieve a microscopically complete resection (R0), (2) to dissect lymphatic and peritoneal surfaces originating from the embryonic dorsal and ventral mesogastrium in order to reduce local recurrence and adequate staging, and (3) restore gastrointestinal continuity. A complete discussion of all the technical details of gastric resection and reconstruction is beyond the scope of this chapter. However, specific surgical issues of oncologic significance are addressed here, including the extent of gastrectomy, extent of regional lymph node dissection, and role of partial pancreatectomy and splenectomy. Additional technical details can be found in surgical atlases and the section “Technical Treatment-Related Issues.”
Extent of Resection for Mid- and Distal Gastric Cancers. The extent of gastrectomy required for satisfactory primary tumor treatment depends primarily on the gross and microscopic status of surgical margins. For most clinical situations, a 5-cm grossly negative margin around the tumor and microscopically negative surgical margin (R0) are the treatment goals. When gastrectomy is performed with curative intent, intraoperatively frozen section assessment of proximal and distal resection margins should be used to improve the likelihood that an R0 resection has been attained. Three relatively small prospective RCTs have compared total gastrectomy with partial (subtotal) gastrectomy for distal gastric cancer.112,113 Overall morbidity, mortality, and oncologic outcome were comparable in each of these RCTs. When the general oncologic goal of an R0 resection can be achieved by a gastric-preserving approach, partial gastrectomy is preferred over total gastrectomy because total gastrectomy is associated with inferior long-term quality of life compared to distal-subtotal gastrectomy. This is particularly relevant for distal gastric cancers, for which a gastric-preserving R0 approach may minimize the risks of specific sequelae of total gastrectomy such as early satiety, weight loss, and the need for vitamin B12 supplementation.
Таблица 53.5. Адъювантная/неоадъювантная терапия рака желудка: клинические исследования III фазы
|Клиническое исследование||Число пациентов||3-y DFS (%)||Overall 5- y Survival (%)|
|Adjuvant S-1 (12 mo)||529||72||80|
|Adjuvant PELF (cisplatin, epirubicin, leucovorin, and 5-FU)||130||43a||48|
|Capecitabine and oxaliplatin||520||74||78|
|Perioperative chemotherapy (ECF)||250||38||36|
|Perioperative chemotherapy (CF)||113||40||38|
|FLOT (docetaxel 50 mg/m2, oxaliplatin 85 mg/m2, leucovorin 200 mg/m2, and 5-FU 2,600 mg/m2)||
|Adjuvant chemoradiation (5-FU–based)||281||48||50b|
|Capecitabine and cisplatin||228||74||73c|
|Capecitabine, cisplatin, and radiation||230||78||75c|
|Pre- and postoperative chemotherapy: ECC/EOC||393||NA||41.3|
|Preoperative ECC/EOC and postoperative chemoradiation (45 Gy in 25 fractions combined with weekly cisplatin and daily capecitabine)||395||NA||40.9|
Note: Additional older trials are mentioned in the text.
a Five-year DFS.
b Five-year overall survival.
c Seven-year overall survival.
DFS, disease-free survival; ACTS-GC, adjuvant chemotherapy trial of TS-1 for gastric cancer; GOIRC, Gruppo Oncologico Italiano di Ricerca Clinica; 5-FU, 5-fluorouracil; MAGIC, Medical Research Council Adjuvant Gastric Infusional Chemotherapy; ECF, epirubicin, cisplatin, and fluorouracil; CF, cisplatin and fluorouracil; ACCORD, the French Action Clinique Coordonnées en Cancérologie Digestive; FLOT4, 5-FU, leucovorin, oxaliplatin and docetaxel; ECX, epirubucin, cisplatin and capecitabin; NA, not available; INT, Intergroup Trial; ECC/EOC, epirubicin, cisplatin/oxaliplatin, and capecitabine.
Extent of Resection for Proximal Gastric Cancer. There are many choices for surgical management of adenocarcinomas arising at the EGJ or in the proximal stomach (Siewert types II and III). Many abdominal surgeons have advocated transabdominal approaches with resection of the lower esophagus and proximal stomach or total gastrectomy. Surgeons trained in thoracic surgery have frequently advocated a combined abdominal and thoracic procedure (often termed esophagogastrectomy) with an intrathoracic or cervical anastomosis between the proximal esophagus and the distal stomach, or a procedure termed transhiatal (or blunt) esophagectomy (THE), which involves resection of the esophagus and EGJ with mediastinal dissection performed in a blunt fashion through the esophageal hiatus of the diaphragm. When THE is performed for adenocarcinoma of the EGJ, gastrointestinal continuity is restored by low cervical anastomosis of the stomach (usually advanced through the esophageal bed in the posterior mediastinum) to the cervical esophagus. Selection among the options has been dependent primarily on individual surgeon training and experience.
The optimal surgical procedure for patients with localized tumors of the EGJ and proximal stomach is a matter of considerable debate. A Dutch RCT compared transthoracic esophagogastrectomy (TTEG, with abdominal and thoracic incisions) with THE in 220 patients with adenocarcinoma of the esophagus and EGJ.114 Although this trial was designed for patients with esophageal cancer, 40 (18%) of the patients had adenocarcinomas of the EGJ (Siewert type II), and the operations evaluated are among those considered for patients with Siewert type II or III cancers. Perioperative morbidity was higher after THE, but there was no significant difference in in-hospital mortality compared with TTEG. Although median OS, DFS, and quality-adjusted survival did not differ significantly between the groups, there was a trend toward improved OS at 5 years with TTEG. These results are judged equivocal, and there is currently no consensus on the optimal surgical approach for patients with Siewert type II tumors. The long-term survival data showed no difference in OS between THE and TTEG. However, compared with THE, TTEG for Siewert type I tumors shows a trend toward better 5-year survival. Patients with a limited number of positive lymph nodes (one to eight) in the resection specimen seem to benefit from TTEG.115,116
Until additional RCTs are performed, the surgical approach to these patients will continue to be individualized and determined by a constellation of factors including surgeon factors (training and experience), patient factors (age, comorbid conditions, and functional status), and tumor factors (pretreatment T and N stage).
Extent of Lymphadenectomy. There has been intense debate surrounding the extent of lymphadenectomy. It involves at least two important issues: (1) adequate staging in terms of the number of lymph nodes resected surgically and examined pathologically and (2) adequate therapy (i.e., do some forms of lymphadenectomy result in better outcomes).117–120
Single-institution reports suggest that the number of pathologically positive lymph nodes is of prognostic significance and that removal and pathologic analysis of at least 15 lymph nodes is required for adequate pathologic staging. Indeed, the current AJCC staging system accounts for these issues and therefore requires analysis of ≥16 lymph nodes to assign a pathologic N stage. Traditionally, D1 dissection (perigastric lymphadenectomy) was the standard of care in Europe and North America, whereas a more radical, D2 dissection including the second echelon lymph nodes is the standard of care in Eastern Asia. The possible therapeutic benefit of extended lymph node dissection D2 versus D1 dissection has been the focus of six RCTs, which are summarized in Table 53.4. These trials were performed because retrospective and prospective nonrandomized evidence suggested that extended lymph node dissection may be associated with improved long-term survival. The RCTs tested the hypothesis that removal of additional pathologically positive lymph nodes (not generally removed as part of a standard D1 lymph node dissection) improves survival. The larger RCTs attempted to follow what are referred to as the “Japanese rules” for lymph node classification and dissection that govern the extent of nodal dissection required based on anatomic location of the primary tumor. Using these Japanese definitions, the RCTs compared limited lymphadenectomy of the perigastric lymph nodes (D1 dissection) to en bloc removal of second echelon lymph nodes (D2 dissection) including removal of the embryonic dorsal and ventral mesogastrium, distal (left) pancreas, and spleen. At least two of the completed trials are underpowered for their primary end point, OS. The trials from the Medical Research Council (MRC) of the United Kingdom257 and the Dutch Gastric Cancer Group121 have received the most attention and discussion.
The MRC trial registered 737 patients with gastric adenocarcinoma; 337 (46%) patients were ineligible by staging laparotomy because of advanced disease, and 400 (54%) patients were randomized at the time of laparotomy to undergo D1 (200) or D2 (200) lymph node dissection. Postoperative morbidity was significantly greater in the D2 group (46% versus 28%, P < .001), and in-hospital mortality rates were also significantly higher in the D2 group than in the D1 group (13% versus 6%, P < .04).257 The most frequent postoperative complications were related to anastomotic leakage (D2 26% versus D1 11%), cardiac complications (8% versus 2%), and respiratory complications (8% versus 5%). The excess morbidity and mortality seen in the D2 group were thought to be related to the routine use of distal (left) pancreatectomy and splenectomy. Partial pancreatectomy and splenectomy were performed to maximize clearance of lymph nodes at the splenic hilum, primarily for patients with proximal tumors; however, many surgeons now believe that adequate lymph node dissection can be performed with pancreas- and spleen-preserving techniques. Long-term follow-up analysis of patients in the MRC trial demonstrated comparable 5-year OS rates of 35% and 33% in the D1 and D2 dissection groups, respectively. Survival based on death from gastric cancer as the event was also similar in the D1 and D2 groups (HR, 1.05; 95% CI, 0.79 to 1.39), as was recurrence-free survival (HR, 1.03; 95% CI, 0.82 to 1.29). The authors concluded that classic D2 lymphadenectomy (with partial pancreatectomy and splenectomy) offered no survival advantage over D1 lymphadenectomy.
The Dutch Gastric Cancer Group conducted a larger RCT with optimal surgical quality control comparing D1 to D2 lymph node dissection for patients with gastric adenocarcinoma that was updated in 2010 after 15-year follow-up.122 Between 1989 and July 1993, 1,078 patients were entered, of whom 996 patients were eligible; 711 patients were randomized to D1 dissection (n = 380) or D2 dissection (n = 331). To maximize surgical quality control, all operations were monitored.122 Initially, this oversight was done by a Japanese surgeon who trained a group of Dutch surgeons, who in turn acted as supervisors during surgery at 80 participating centers. Notwithstanding the extraordinary efforts to ensure quality control of the two types of lymph node dissection, both noncompliance (not removing all lymph node stations) and contamination (removing more than was indicated) occurred, thus blurring the distinction between the two operations and confounding the interpretation of the oncologic end points. The postoperative morbidity rate was higher in the D2 group (43% versus 25%, P <.001), the reoperation rate was also higher at 18% (59 of 331) versus 8% (30 of 380), and the mortality rate was also significantly higher in the D2 group (10% versus 4%, P = .004). Patients treated with D2 dissection also required a longer hospitalization. As in the MRC trial, partial pancreatectomy and splenectomy were performed en passant in the D2 group. Five-year survival rates were similar in the two groups: 45% for the D1 group and 47% for the D2 group (95% CI for the difference, −9.6% to 5.6%). The subset of patients who had R0 resections, excluding those who died postoperatively, had cumulative risks of relapse at 5 years of 43% with D1 dissection and 37% with D2 dissection (95% CI for the difference, −2.4% to 14.4%).
The Dutch investigators concluded that there was no role for the routine use of D2 lymph node dissection in patients with gastric cancer. At 15-year follow-up, 174 of 711 (25%) patients were alive, all but 1 without recurrence. The OS was 21% (82 of 711) and 29% (92 patients) for the D1 and D2 groups, respectively (P = .34). Interestingly, gastric cancer–specific death was higher in the D1 group at 48% (182 of 380) versus 37% (123 of 331). Local recurrence was higher in the D1 group at 22% (82 of 380) versus 12% (40 of 331), and regional recurrence was higher in the D1 group at 19% (73 of 380) versus 13% (43 of 331). The authors concluded that after 15 years of follow-up, D2 lymphadenectomy is associated with lower locoregional recurrence and gastric cancer–specific death rates than D1 lymphadenectomy. D2 resection is also associated with higher postoperative mortality, morbidity, and reoperation rates. Examining the results after 15-year follow-up and given the data regarding gastric cancer–specific mortality, local recurrence, and regional recurrence, the authors revised their original conclusion: “Because spleen-preserving D2 resection is safer in high-volume centers, it is the recommended surgical approach for patients with potentially curable gastric cancer.”122
Degiuli et al.123 reported on the Italian Gastric Cancer Study Group experience with a prospective randomized trial comparing pancreas-sparing D1 versus D2. There were 76 patients randomized to undergo D1 and 86 patients to D2 resections. Complication rates were higher in the D2 group: 16.3% versus 10.5%. Postoperative mortality was higher in the D1 group: 1.3% versus 0% in the D2 group. The authors concluded that in experienced hands, the morbidity and mortality can be as low as shown by Japanese surgeons. Long-term survival was similar (66.5% versus 64.2% for D1 and D2 lymphadenectomy, respectively; P = .695). However, whereas the D1 lymphadenectomy showed improved DFS for pT1N0 tumors, D2 showed improved survival in patients with pT2 to pT4 or patients with N1 disease.124 A meta-analysis of clinical trials comparing D1 and D2 lymphadenectomy was performed by Memon et al.125 Six trials totaling 1,876 patients (D1 = 946, D2 = 930) were analyzed.125 Meta- analysis showed that D1 gastrectomy is associated with significantly fewer anastomotic leaks and decreased postoperative complication rate, reoperation rate, length of hospital stay, and 30-day mortality rate, whereas the 5- year survival in D1 gastrectomy patients was similar to the D2 cohort. Wu et al.126 reported on a randomized trial comparing D1 versus D3 dissections. There were no operative deaths, and morbidity was only 12%. At median follow-up of 94.5 months, D3 showed better 5-year OS of 59.5% (95% CI, 50.3 to 68.7) versus 53.6% (95% CI, 44.2 to 63.0; P = .041), and a trend toward better DFS at 5 years: 40.3% versus 50.6% (P = .197). Only 13% had pancreas or splenic resection as compared with 23% in the Dutch trial. The authors concluded that D3 as compared to D1 offers survival benefit. As far as the authors of this chapter understand, this is the first RCT to demonstrate survival advantage for more extensive lymphadenectomy (D3). As such, it requires careful examination. Roggin and Posner127 have critically reviewed the work by Wu et al.126 One controversial element of this trial was the use of OS versus gastric cancer–specific survival; 17 of 111 (15%) of the reported deaths were not related to tumor recurrence, resulting in very small survival benefit.
Interpretation of the existing level 1 evidence is encumbered by a number of issues that have been discussed in detail elsewhere. The primary concerns relate to whether (1) the increased operative mortality associated with protocol-mandated partial pancreatectomy and splenectomy for patients with proximal tumors undergoing D2 dissection prevented identification of a potential therapeutic impact of extended lymph node dissection and (2) the phenomena of noncompliance and contamination led to homogenization of the operative procedures to such an extent that the fundamental hypothesis was not tested. Owing to these interpretation issues, the question of a possible therapeutic benefit of D2 dissection remains unsettled.
Many Japanese gastric surgeons have considered the caveats associated with the MRC and Dutch trials and believe that, notwithstanding inherent patient selection and stage migration biases, the existing retrospective data provide sufficient proof of a clinical benefit of D2 dissection. On this basis, D2 or less aggressive lymphadenectomy (stations 1 to 9 or 2 to 9) with spleen and distal pancreas sparing (D1+) dissection has been adopted as the standard of care for patients with localized, higher risk gastric cancer in most centers in East Asia and some specialized centers in the West. The Japanese Clinical Oncology Group (JCOG-9501) has investigated an even more aggressive surgical approach in an RCT evaluating standard D2 versus D2+ (para-aortic node dissection [PAND]) in the management of completely resected (R0) T2 to T4 gastric cancer.128,129 Patients (n = 523) were randomized intraoperatively to undergo D2 lymphadenectomy alone (263 patients) or D2 lymphadenectomy plus PAND (260 patients). The primary end point was OS. Postoperative morbidity was higher in the PAND group (28% versus 21%, P = .07), and mortality was similar at 0.8% in each group. Five-year OS for patients undergoing PAND was 70.3% versus 69.2% (HR, 1.03; P = .85). There was no significant difference in recurrence-free survival. The authors concluded that, as compared to D2 lymphadenectomy, PAND when added to D2 lymphadenectomy does not improve survival rates.
Another Japanese study compared D2 with extended PAND (D4).130 This trial randomized patients to undergo gastrectomy with D2 (n = 135) or D4 (n = 134) lymphadenectomy. The 5-year survival rates were 52.6% versus 55%, respectively (P = .8). The authors concluded that prophylactic D4 dissection is not recommended. In an RCT, a Western group from Poland investigated D2 dissection versus extended D2 dissection defined according to the Japanese Gastric Cancer Association classification.131 They randomized 275 patients with gastric cancer to gastrectomy with D2 (n = 141) versus D2 + lymphadenectomy (n = 134). The overall postoperative morbidity and mortality were similar and did not differ statistically. Survival data are not available at this time. Thus, the limits of radical surgery have been reached in Japan and the pendulum has swung back toward D2 dissection in clinical settings in which this can be safely performed.
In summary, lymph nodes should be considered as indicators that the gate was opened rather than as the gate keepers for cure. None of the prospective RCT trials executed in the West demonstrated survival advantage for more extensive lymphadenectomy. However, none of these studies were powered enough to detect single-digit difference in 5-year OS. Several non–a priori planned subgroup analyses were done and showed some survival advantage for certain subgroups. These analyses cannot be used to form evidence-based medicine but should be used to form hypotheses for further RCT studies. In high-volume specialty centers, spleen- and pancreas- preserving D2 dissection (D1+) is performed safely and can potentially result in decreased gastric cancer–specific mortality based on 15 years of follow-up from the Dutch study.122
Another systematic review and meta-analysis of eight RCTs encompassing over 2,000 patients (D1, n = 1,042; D2, n = 1,002) evaluated the safety and efficacy of extended lymphadenectomy in gastric cancer. A significant increase in operative morbidity and mortality was evident in patients undergoing extended D2 lymphadenectomy, with a trend in decreased disease-specific mortality in those having spleen- and pancreas-preserving gastrectomy. Longer term survival is required to ascertain oncologically relevant outcome benefit with D2 gastrectomy.132–139
Partial Pancreatectomy and Splenectomy Resect or Preserve? Partial (left, distal) pancreatectomy and splenectomy have been performed as part of D2 lymph node dissection to remove the lymph nodes along the splenic artery (station 11) and lymph nodes within the splenic hilum (station 10), primarily for patients with tumors located in the proximal and mid-stomach. Indeed, partial pancreatectomy and splenectomy were required for patients with proximal tumors in the D2 arm of the Dutch and MRC RCTs but were required only for direct tumor extension in the D1 arm. In the Dutch and MRC D1 versus D2 randomized trials, splenectomy was associated with increased risk of surgical complications and operative mortality. In addition, a multivariate analysis suggested that splenectomy is associated with inferior long-term survival. The frequent performance of splenectomy (e.g., 30% of patients in the D2 arm versus 3% in the D1 arms of the Dutch trial) in the patient undergoing extended D2 lymphadenectomy, with its associated adverse effects on both short- and long-term mortality, confounds the interpretation of the Dutch and MRC RCTs. Thus, the hypothesis that spleen- and pancreas-preserving D2 lymph node dissection improves survival remains unproven. There is an evolving consensus that splenectomy should be performed only in cases with intraoperative evidence of direct tumor extension into the spleen, or its hilar vasculature, or when the primary tumor is located in the proximal stomach along the greater curvature. Partial pancreatectomy should be performed only in cases of direct tumor extension to the pancreas.136
Recent reports have described pancreas- and spleen-preserving forms of D2 dissection.140,141 This organ- preserving modification of classic D2 dissection allows for dissection of some station 11 and 10 lymph nodes without the potential adverse effects of pancreatectomy and/or splenectomy. In a small single-institution RCT recently reported from Chile, Csendes et al.142 randomized 187 patients with localized proximal gastric adenocarcinoma to treatment by total gastrectomy with D2 lymph node dissection plus splenectomy or total gastrectomy with D2 lymphadenectomy alone. Operative mortality was similar in both groups (splenectomy group, 3%; control group, 4%). However, septic complication rates were higher in the splenectomy arm than in the control arm (P < .04). There was no difference in 5-year OS between study groups, although it is not clear that the trial was designed with survival as the primary end point. Other investigators confirmed these findings.136,143
The JCOG conducted a multi-institutional RCT (JCOG-0110-MF) comparing D2 dissection with and without splenectomy for patients diagnosed with proximal gastric cancer. The hypothesis to be tested is that 5-year OS of patients treated by extended D2 dissection without splenectomy (n = 251) is 5% less than that of patients treated by D2 dissection with splenectomy (n = 254). The study showed no added value in survival to splenectomy in D2 lymphadenectomy, whereas the estimated blood loss during surgery as well as postoperative complications were higher.144
Минимально инвазивная хирургия для рака желудка
The understanding that the “classical” D2 dissection with splenectomy and distal pancreatectomy can be replaced by a spleen- and pancreas-preserving lymphadenectomy as well as the understanding that bursectomy is not always mandatory in gastric cancer patients led the way to explore minimal invasive surgery (MIS) for the treatment of gastric cancer. Eight prospective clinical trials from Korea, Japan, and China and a small-scale trial from Italy showed that laparoscopic D2 gastrectomy (LADG) is feasible, safe with improved short-term outcomes and not inferior to open distal gastrectomy (ODG) for EGC patients, although it is still controversial for locally advanced gastric cancer patients. Laparoscopic total gastrectomy is performed only selectively in very experienced centers.145
A meta-analysis including 3,411 patients from nonrandomized trials and randomized clinical trials showed that the number of lymph node retrieved was close, postoperative complications were lower in LADG compared to ODG, with shorter hospital stay and similar OS.
They concluded that in experienced surgical centers, LADG is feasible with postoperative recovery. However, the current evidence cannot exclude the benefits or harms especially in node- positive patients.146
An earlier meta-analysis was conducted, including only prospective randomized trials, with nearly 1,500 patients assessing the feasibility and safety of laparoscopic total gastrectomy with D2 lymphadenectomy compared to the same operation done in the standard open manner. The laparoscopic technique was associated with significantly longer operative time, less operative blood loss, fewer analgesic requirements, earlier return of bowel function, shorter hospital stay, and reduced operative morbidity. The total number of lymph nodes removed
surgically and analyzed pathologically as well as operative mortality was not significantly different between groups. Further well-designed clinical RCTs are warranted to define the role of laparoscopic gastrectomy and extended lymphadenectomy for gastric adenocarcinoma.
Laparoscopy clearly has a role in the complete staging of disease in patients with gastric adenocarcinoma and the detection of radiologically occult macroscopic, or microscopic peritoneal cytology positive-only metastasis. Laparoscopy and peritoneal cytology are important for accurate staging and the detection of occult metastatic disease. This methodology adds value to modern imaging techniques, for positive microscopic peritoneal cytology-only disease is tantamount to macroscopic M1 disease in terms of oncologic outcome.
Адъювантная внутрибрюшинная химиотерапия
Peritoneal recurrence is a common pattern of failure for patients with gastric cancer, even after curative resection. The median survival time of patients with peritoneal recurrence is 3 to 6 months. The rationale is based on the observation that drug concentrations within the peritoneal cavity are much higher than those achievable by intravenous or oral drug administration. The data are a mixture of retrospective reviews, pilot phase II trials, and several small phase III trials. No definitive conclusions can yet be drawn regarding the effectiveness of intraperitoneal postoperative chemotherapy in this setting.149
There are several modes of administering intraperitoneal chemotherapy: hyperthermic intraoperative peritoneal chemotherapy (HIPEC), normothermic intraoperative intraperitoneal chemotherapy (NIIC) given at the conclusion of the operation, early postoperative intraperitoneal (normothermic) chemotherapy (EPIC), or delayed postoperative intraperitoneal (normothermic) chemotherapy. The theoretical advantage of intraoperative treatment is better drug distribution and the ability to use hyperthermia (HIPEC) to enhance microscopic tumor cytotoxicity. Most trials in gastric cancer have used either 5-FU or floxuridine, mitomycin C, or cisplatin for intraperitoneal chemotherapy. Yan et al.150 performed a meta-analysis of the RCTs reporting on adjuvant intraperitoneal chemotherapy for patients undergoing curative gastric resection; 10 trials involving 1,474 patients were included. A total of 775 patients had resection alone, and 873 patients had resection plus intraperitoneal treatment. A significant improvement in survival was associated with HIPEC (HR, 0.6; 95% CI, 0.43 to 0.83; P = .002) or HIPEC plus EPIC (HR, 0.45; 95% CI, 0.29 to 0.68; P = .0002). There was only a trend toward survival benefit with NIIC (P = .06), but this was not significant with either EPIC alone or delayed postoperative intraperitoneal (normothermic) chemotherapy. The authors concluded that HIPEC with or without EPIC after curative gastric resection is associated with modest improvement in survival and increased complication rate.
Kang et al.151 reported on 640 patients with serosal-positive gastric cancer who underwent resection and were then randomized to receive intravenous mitomycin C (20 mg/m2) at 3 to 6 weeks after surgery and oral doxifluridine (460 to 600 mg/m2/day) starting 4 weeks after the administration of mitomycin C and continuing for 3 months or to receive intraoperative intraperitoneal cisplatin (100 mg), intravenous mitomycin C (15 mg/m2) on postoperative day 1, followed by oral doxifluridine for 12 months, and six monthly intravenous cisplatin (60 mg/m2). Results indicated potential improvement in progression-free survival (PFS) and OS for the intraperitoneal cisplatin therapy arm. Kuramoto et al.152 reported in a retrospective fashion that extensive intraperitoneal lavage performed with 10 L of normal saline after curative resection and before NIIC is superior to surgery alone or to surgery plus NIIC.153,154
A recent international multidisciplinary expert panel created statements to define processes of care relevant to the perioperative management of patient with gastric cancer. Ten processes were deemed essential to maintaining quality of care:
- CT of the chest, abdomen, and pelvis is part of preoperative staging.
- PET scans are not routinely indicated.
- Adjuvant and neoadjuvant therapy should be considered.
- Clinical trials should be conducted and patients considered for participation.
- Treatment decision making should involve a multidisciplinary team.
- Hospitals must have sufficient systems in place to support the care of patients with gastric cancer.
- Sixteen or more lymph nodes should be resected and staged pathologically.
- Surgery should only be performed to palliate major symptoms in the setting of metastatic disease.
- Surgeons experienced in the treatment of gastric cancer should be performing the operations.
- These surgeons should also have advanced laparoscopic surgery experience for laparoscopic gastric resection.
These processes were deemed to be of indeterminate necessity for maintaining quality of care:
- Diagnostic laparoscopy before treatment
- Multidisciplinary approach to patients with linitis plastica
- Genetic testing for diffuse gastric cancer, family history, or age younger than 45 years at time of diagnosis
- Endoscopic removal of select T1a N0 lesions
- D2 lymphadenectomy in curative intent cases
- D1 lymphadenectomy for EGC or patients with comorbidities
- Frozen section analysis of gastric resection margins
- Nonemergent cases performed in a hospital with a volume of >15 gastric cancer resections per year
- By a surgeon who performs more than six gastric resections per year
Individualized assessments of lymph node involvement. Recent attention has focused on methods of individual assessment of risk of lymphatic spread. These techniques offer the possibility of tailoring surgical therapy for an individual patient based on clinicopathologic risk assessment of the primary tumor and/or preoperative or intraoperative identification of SLNs, or primary draining lymph nodes. At present, at least three approaches to individual nodal risk assessment have been evaluated: computer modeling, preoperative endoscopic peritumoral injection, and SLN biopsy.155,156
Preoperative computer modeling of individual patient nodal involvement. Kampschöer et al.157 developed a computer program to estimate the probability of spread to specific nodal regions for an individual patient using his or her pretreatment clinicopathologic data. The program incorporated data on tumor size, depth of infiltration, primary tumor location, grade, type, and macroscopic appearance of primary tumors from 2,000 patients with surgically resected gastric cancers treated at the National Cancer Center of Tokyo. The data set used for matching individual patient data is continuously updated and now includes >8,000 patients. This computer model has been validated in non-Japanese patients in Germany158 and Italy.159 In the United States, Hundahl et al.160 retrospectively applied this computer model to evaluate the surgical treatment of patients entered into the intergroup trial of adjuvant 5-FU–based chemoradiation. The Kampschöer et al.157 program was used to estimate the likelihood of disease in undissected regional node stations, defining the sum of these estimates as the Maruyama index of unresected disease. A total of 54% of participating patients underwent D0 lymphadenectomy. The median index was 70 (range, 0 to 429). In contrast to D level, the Maruyama index proved to be an IDPF of survival, even with adjustment for the potentially linked variables of T stage and number of positive nodes. More recent and smaller studies confirmed these findings.161–163
Предоперационная эндоскопическая перитуморальная инъекция. The hypothesis that peritumoral injection of compounds designed to optimize lymph node dissection improves lymph node clearance was addressed in a small RCT evaluating preoperative endoscopic vital dye staining with CH40 prior to D2 dissection. The frequency of positive lymph nodes in patients injected with CH40 before D2 dissection was greater than that observed in patients treated by D2 dissection alone. This approach optimized the yield of lymph node dissection presumably by directing surgeons to include specific lymph nodes in the dissection that might have otherwise been left in situ and/or by directing pathologists to examine specific areas of the lymphadenectomy specimens. Further prospective studies of this approach are required to confirm the feasibility of this technique and to assess its impact on intraoperative decision making regarding the extent of lymphadenectomy and accuracy of specimen dissection and nodal retrieval in anatomic pathology.
Биопсия сторожевых лимфоузлов при раке желудка. The goal of SLN biopsy is to identify the node or nodes believed to be the first peritumoral lymph nodes in the orderly spread of gastric adenocarcinoma from the primary site to the regional lymph nodes. Sampling of this lymph node(s) may allow for prediction of the nodal status of the entire lymph node basin, possibly obviating extended nodal dissection and its attendant morbidity in patients found to have a negative SLN. Recent pilot studies have evaluated the feasibility, sensitivity, and specificity of SLN biopsy for patients with gastric cancer.164–173 These pilot studies demonstrated that SLN identification is feasible in approximately 95% of patients. However, most patients with gastric cancer have multiple “sentinel” nodes, with mean numbers of SLNs per patient ranging from 2.6 to 6.3. The aggregate experience to date suggests that among patients with pathologically involved lymph nodes, SLN results in false-negative assessment of pathologic regional nodal status in 11% to 60% of patients. Thus, the preliminary data available suggest that SLN biopsy cannot reliably replace lymph node dissection as a means of accurately staging regional nodal basins in gastric adenocarcinoma.174
In a large study of nearly 400 patients, the ability and accuracy of SLNs was examined in a prospective, multicenter phase II study.175 Patients with early T-stage gastric cancer (cT1 or cT2, tumor <4 cm) were evaluated with SLN mapping, followed by gastrectomy and D2 lymph node dissection. The SLN mapping technique identified 57 patients who had nodal involvement, of which 53 had true positive SLNs, resulting in 99% accuracy. Although further validation is needed, these results are quite encouraging.76
The JCOG multicenter trial (JCOG-0302) assessed the feasibility and accuracy of indocyanine green (ICG) SLN mapping at time of surgery prior to gastrectomy and lymphadenectomy for EGC (T1).176 Single sections of ICG-stained SLNs were examined intraoperatively using frozen section with hematoxylin and eosin stain. The primary study end point was the proportion of false-negative SLNs. Study accrual was halted after 440 of the planned 1,550 patients were enrolled when the proportion of false negatives was found to be unexpectedly and unacceptably high (46%). The authors appropriately concluded that SLN mapping and biopsy using ICG and intraoperative single nodal frozen section evaluation using hematoxylin and eosin staining is inappropriate for clinical use in EGC.
Volume-Outcome Relationships for Gastrectomy. Recent studies have established a clear relationship between institutional gastrectomy volume and perioperative mortality rates—the so-called volume-outcome relationship. The recent analysis of a national database by Birkmeyer et al.177–179 of 31,854 patients who underwent gastrectomy between 1994 and 1999 demonstrated an inverse relationship between institutional gastrectomy volume and operative mortality rates. The odds ratio for gastrectomy-related death was lowest among patients treated within hospitals in the highest gastrectomy volume quintile (odds ratio,0.72; 95% CI, 0.63 to 0.83). A separate analysis evaluating surrogate end points for morbidity demonstrated that gastrectomy at high- volume centers was associated with the shortest duration of hospital stay and the lowest readmission rates.180–183 Similar findings were noted by Hannan et al.184 in an analysis of the New York State Department of Health’s administrative database. Their analysis of 3,711 patients who underwent gastrectomy between 1994 and 1997 included adjustments for covariates such as age, demographic variables, organ metastasis, socioeconomic status, and comorbidities. Patients who had a gastrectomy at hospitals in the highest volume quartile had an absolute risk- adjusted mortality rate that was 7.1% (P < .0001) lower than those treated at hospitals in the lowest volume quartile, although the overall mortality rate for gastrectomy was only 6.2%.185
These studies demonstrate that the risk-adjusted mortality rates for gastrectomy are significantly lower when gastrectomy is performed by high-volume providers.186–189 It is likely that the variations in gastrectomy-related mortality rates relate in part to surgeon training and their patient age-volume and experience with the procedure. Data on gastrectomy volume obtained from general surgeons undergoing recertification after a minimum of 7 years in practice demonstrate that the mean number of gastric resections performed by recertifying general surgeons in the United States is only 1.4 per year. Thus, given the data supporting a relationship between hospital and provider volumes and the morbidity and mortality rate of gastric resection, there are reasons to consider regionalization of the surgical treatment of gastric cancers.
Outcome in Japan versus Western Countries. Stage-stratified survival rates for gastric adenocarcinoma are higher in Japan than in most Western countries. The reasons for this are complex, are incompletely understood, and cannot be fully addressed within the context of a chapter covering all aspects of gastric cancers.
Important differences in the epidemiology of gastric cancer may contribute to observed differences in outcome in Japan versus Western countries. First, the better prognosis intestinal-type (Laurén classification) tumors are seen more commonly in Japan, whereas the diffuse-type cancers (poorer prognosis) are more frequent in Western series. These regional differences in the frequencies of intestinal and diffuse cancers are believed to be related to the higher incidence of H. pylori infection and atrophic gastritis in Japan. Second, poorer prognosis proximal gastric cancers are less frequent in Japan. Indeed, the progressive increase in proximal gastric cancers observed in the West has not been observed in Japanese populations.
Regional differences in the diagnostic criteria for EGC also may contribute to regional differences in observed outcome. In Japan, gastric carcinoma is diagnosed based on its structural and cytologic features without consideration of invasion of the lamina propria. In contrast, Western pathologists consider invasion of the lamina propria to be an essential element of the diagnosis of carcinoma. As a consequence, unequivocally neoplastic noninvasive lesions are classified as carcinoma in Japan but as dysplasia by Western pathologists. To overcome these differences, the Padova190 and Revised Vienna191 classifications have recently been proposed. However, until there is worldwide consensus and implementation of uniform diagnostic criteria for EGC, comparative assessments of the outcome of patients with EGC treated in Japan and Western countries should acknowledge the selection bias associated with different diagnostic criteria.
Stage migration is a well-documented factor contributing to the stage-specific differences in outcome between Japanese and Western patients. Stage migration arises because there is widespread use of extensive D2 or D3 lymphadenectomy combined with rigorous pathologic assessment of the lymphadenectomy specimen in Japan. More accurate stage assignment of Japanese patients leads to secondary stage migration—improvement in stage- specific survival without improvement in OS. The frequency and impact of stage migration were quantified by the Dutch Gastric Cancer Group in their RCT comparing D1 and D2 lymph node dissection. Stage migration occurred in 30% of patients in the D2 group, and the stage-specific decreases in survival rates attributable to stage migration were 3% for AJCC/UICC stage I disease, 8% for stage II, 6% for stage III, and 12% for stage IIIB, with the more accurately staged D2 group having higher survival rates.192
In addition to regional differences in epidemiology, diagnostic criteria for EGC, and stage migration, other factors may contribute to the observed differences in stage-stratified survival. Such factors may include genetic, environmental, and biologic differences between Japanese and Western patients and tumors. These factors have been less well studied but were addressed in a comprehensive review by Yamamoto et al.193
Outcome in Korea versus Western Countries. A separate evaluation was performed comparing gastric cancer survival following curative intent resection in Korea versus the United States.193–195 This study compared two independent, single-institution prospectively maintained databases from 1995 to 2005: one from MSKCC (n = 711 curatively resected patients who did not receive neoadjuvant therapy) and another from St. Mary’s Hospital in Seoul, South Korea (n = 1,646 patients, also curatively resected without receiving preoperative therapy). All patients had a D2 dissection and adequate nodal staging. There were notable differences in the two cohorts: Patients from the United States were more likely to have proximal tumors and more advanced stage compared with patients resected in Korea. However, when controlling for all known risk factors, stage for stage, patients from Korea still had better OS (HR, 1.3; 95% CI, 1.0 to 1.7; P = .05). These data cannot exclude differences in underlying cancer biology as a potential explanation for the observed differences in survival in gastric cancer between patients treated in Korea versus those treated in the United States.
Adjuvant therapy refers to the administration of treatment following a potential curative resection. However, as recovery after gastrectomy may be prolonged, adjuvant therapy is often delayed or avoided. Neoadjuvant therapy involves the use of treatment before potentially curative surgery and has three advantages: higher compliance rates, potential downstaging of the tumor facilitating a higher rate of R0 resections, and earlier treatment of micrometastatic disease. Perioperative therapy refers to a combination of neoadjuvant and adjuvant therapies.
Adjuvant Chemotherapy. The results of selected recent RCTs comparing adjuvant chemotherapy with surgery alone are summarized in Table 53.5. The adjuvant chemotherapy trial of TS-1 for gastric cancer (ACTS-GC) trial from Japan studied S-1, an oral fluoropyrimidine, in a group of 1,059 patients (stages II to IIIB). S-1 was given for 12 months (4 weeks on/2 weeks off). A total of 529 patients received S-1 plus operation and 530 patients underwent operation only. The 3-year OS was 80.1% and 70.1%, respectively (HR, 0.68),196 and this survival advantage was maintained at 5 years: 71.7% with adjuvant S-1 versus 61.1% with surgery alone (HR, 0.669; 95% CI, 0.540 to 0.828).197 In addition, the CLASSIC trial conducted in Asia reported the results of adjuvant capecitabine and oxaliplatin.198 In this study, patients were required to have a D2 resection, and those with stage II to IIIB were then randomly assigned to receive 6 months (eight cycles) of capecitabine/oxaliplatin or observation. This was a large study, in which 520 patients were randomly assigned to receive adjuvant chemotherapy and 515 to surgery alone. The study met its primary end point of 3-year DFS (74%; 95% CI, 69% to 79% with chemotherapy, versus 59%; 95% CI, 53% to 64% with surgery alone; P < .0001). Estimated 5-year OS was 78% (95% CI, 74% to 82%) in the adjuvant capecitabine and oxaliplatin group versus 69% (95% CI, 64% to 73%) in the observation group.199 In contrast to these positive studies performed in Asia, a number of older studies produced negative results.200–205 For example, in the Gruppo Oncologico Italiano di Ricerca Clinica (GOIRC) trial,204 128 patients were randomized to surgery alone versus 130 patients who received cisplatin, epirubicin, leucovorin, and 5-FU as adjuvant therapy. There was no difference in 5-year DFS (42% versus 43%) or 5-year OS (49% versus 48%), respectively.
Several meta-analyses of adjuvant chemotherapy in gastric cancer have been reported. Buyse et al.206 reported a meta-analysis that included individual patient data; 16 trials involving 3,710 patients were available for analysis. They found an OS benefit in favor of adjuvant chemotherapy (HR, 0.83; 95% CI, 0.76 to 0.91; P < .0001). The absolute benefit was 6.3% at 5 years. The GASTRIC group conducted a meta-analysis including individual patient data from 17 trials involving 3,838 patients. They found an OS benefit in favor of adjuvant chemotherapy (HR, 0.82; 95% CI, 0.75 to 0.90; P > .001). The absolute benefit was 5.9% at 5 years.207 The five most recent trials indicate that adjuvant therapy decreases the risk of recurrence by approximately 10%.207 It is important to note that the extent of lymph node dissection varied greatly among these trials. To summarize, the benefit of adjuvant chemotherapy has only been demonstrated in randomized trials following D2 lymph node dissection. The most effective regimen to use, postoperative or perioperative, chemotherapy alone or combined chemoradiation, is discussed in the following text and is the focus of ongoing clinical research trials.
Adjuvant combined-modality therapy. The recognition of the high rates of local and regional failure following surgery in patterns of failure analyses has served as the rational for the inclusion of radiation therapy in adjuvant/neoadjuvant gastric cancer. Between different studies there is marked variability in radiation dose and schedule, sequence with surgery (preoperatively, intraoperatively, or postoperatively), and the use of concurrent and maintenance chemotherapy. These differences, together with changes in surgical practice and epidemiologic trends, may explain in part the conflicting results observed in phase III studies.
Single-modality radiation, adjuvant or neoadjuvant. Two older randomized phase III trials have studied the use of external-beam radiation therapy (EBRT) alone with surgery.208,209 The British Stomach Cancer Group study published in 1989 demonstrated that radiation improved local control but had a detrimental effect on survival. Of note, one-third of patients randomized to receive adjuvant treatment did not receive the assigned therapy, and 39% had residual microscopic or gross disease at the end of the operation. In contrast, the results of a phase III study from Beijing published in 1998 demonstrated a survival benefit for patients with gastric cardia carcinoma receiving preoperative radiation and surgery versus surgery alone.210 In this study, 370 patients with gastric cardia carcinoma were randomized to 40 Gy in 20 fractions over 4 weeks of preoperative irradiation and surgery or surgery alone. The 5-year survival rates of preoperative radiation and surgery and the surgery-alone group were 30% and 20%, respectively (10-year, 20% and 13%, respectively; P = .009). Further, both local and regional nodal control was improved in patients undergoing preoperative radiation and surgery (61% and 61%, respectively) versus surgery (48% and 45%, respectively) only. Morbidity and mortality rates were not increased in patients receiving preoperative therapy.
Systematic reviews and meta-analysis211,212 have evaluated the benefit of adjuvant/neoadjuvant radiation for resectable gastric cancer. Postoperative radiation was associated with a significant improvement in OS (HR, 0.78; P < .001).
Intraoperative Radiation Therapy. Intraoperative radiation therapy (IORT) technique facilitates the delivery of a single large fraction (10 to 35 Gy) of radiation to the tumor or tumor bed while excluding or protecting surrounding normal tissue. Two randomized trials have examined the efficacy of IORT in combination with surgery for patients with gastric carcinoma.213,214 A randomized study from Japan demonstrated that patients with Japanese stages II to IV disease who received IORT (28 to 35 Gy) in conjunction with resection showed improved survival over patients who underwent resection without radiation.213 A small study performed at the NCI randomized 41 patients (out of 100 screened patients for the study) to receive IORT versus postoperative EBRT to the upper abdomen (50 Gy). Those receiving IORT had improved local control (92% versus 44%), without significant improvement in OS. The implication of IORT has logistical challenges, and based on these results, the use of IORT in gastric cancer remains investigational.
Adjuvant chemoradiation, combined-modality treatment. The Intergroup Trial (INT) 0116 randomized patients to receive surgery alone or surgery plus postoperative 5-FU–based chemotherapy and radiation.215 The trial included patients with stages IB to IVA nonmetastatic adenocarcinoma of the stomach or gastroesophageal junction. After en bloc resection, 556 patients were randomized to either observation alone or postoperative combined-modality therapy consisting of one monthly 5-day cycle of 5-FU and leucovorin, followed by 45 Gy in 25 fractions plus concurrent 5-FU and leucovorin (4 days in week 1, 3 days in week 5) followed by two monthly 5-day cycles of 5-FU and leucovorin. Nodal metastases were present in 85% of the cases. With 5 years of median follow-up, 3-year relapse-free survival was 48% for adjuvant treatment and 31% for observation (P = .001); 3- year OS was 50% for treatment and 41% for observation (P = .005). The median OS in the surgery-only group was 27 months, compared with 36 months in the chemoradiotherapy group; the HR for death was 1.35 (95% CI, 1.09 to 1.66; P = .005). The HR for relapse in the surgery-only group as compared with the chemoradiotherapy group was 1.52 (95% CI, 1.23 to 1.86; P < .001). The median duration of relapse-free survival was 30 months in the chemoradiotherapy group and 19 months in the surgery-only group. Patterns of failure were based on the site of first relapse only and were categorized as local, regional, or distant. Local recurrence occurred in 29% of the patients who relapsed in the surgery-only group and 19% of those who relapsed in the chemoradiotherapy group. Regional relapse, typically abdominal carcinomatosis, was reported in 72% of those who relapsed in the surgery- only group and 65% of those who relapsed in the chemoradiotherapy group. Extra-abdominal distant metastases were diagnosed in 18% of those who relapsed in the surgery-only group and 33% of those who relapsed in the chemoradiotherapy group. Treatment was tolerable, with 3 (1%) toxic deaths. Grade 3 and 4 toxicity occurred in 41% and 32% of cases, respectively. With more than 10 years of median follow-up, the survival advantage was maintained, the HR for OS was 1.32 (P = .0046), and the HR for relapse-free survival was 1.51 (P < .001).216 No increases in late toxicity events were noted. Post hoc subset analyses show robust treatment benefit in most subsets, including different T and N stages, with the exception of patients with diffuse histology who exhibited a minimal nonsignificant treatment effect. Few patients in this trial had T4 disease or underwent D2 dissection. The results of this large study demonstrate a clear survival advantage for the use of postoperative chemoradiation; however, the regimen used in this trial was associated with high rates of gastrointestinal and hematologic toxicities. Infusional 5-FU has generally been replaced with capecitabine, and indeed, the combination of postoperative radiation combined with capecitabine (1,650 mg/m2 daily throughout radiotherapy) has been demonstrated to be well tolerated in a small pilot study.217
Attempts have been made to intensify the chemoradiation regimen. Cancer and Leukemia Group B 80101 compared the INT 0116 regimen with a postoperative ECF (epirubicin 50 mg/m2, cisplatin 60 mg/m2, and continuous infusion 5-FU 200 mg/m2/day for 21 days) prior and following radiation but did not find any survival advantage.218
Role of adjuvant chemoradiation after D2 dissection. To address the important question of the value of postoperative radiation following D2 resection, a Korean phase III “ARTIST” study compared postoperative cisplatin/capecitabine (XP) alone versus postoperative XP with capecitabine and radiation.219 In this study, 458 patients were enrolled, with 228 randomly assigned to receive adjuvant chemotherapy (XP for six cycles) and 230 patients assigned to receive adjuvant chemoradiation (XPx2 → capecitabine and radiation → XPx2). With 7 years of follow-up, DFS remained similar between treatment arms (HR, 0.740; 95% CI, 0.520 to 1.050; P = .09). OS also was similar (HR, 1.130; 95% CI, 0.775 to 1.647; P = .5). Subgroup analyses showed that chemoradiotherapy significantly improved DFS in patients with node-positive disease and with intestinal-type gastric cancer. There was a similar trend for DFS and OS by stage of disease.220 A meta-analysis of 13 clinical trials testing adjuvant/neoadjuvant radiotherapy or chemoradiotherapy for resectable gastric cancer (including the ARTIST trial) published in 2012 was unable to identify a subgroup of patients that does not benefit from adjuvant radiotherapy, whether based on geographical region, timing of radiation, the extent of nodal dissection performed, or nodal status.211
The ongoing ARTIST 2 is a three-arm phase III trial among patients with positive lymph nodes following D2 dissection. The trial compares adjuvant chemotherapy involving S-1 for 1 year (arm A) with S-1 plus oxaliplatin for eight cycles (arm B) and chemoradiotherapy (arm C). Arm C patients receive S-1 plus fixed dose oxaliplatin (SOX) for two cycles, then concurrent chemoradiotherapy 45 Gy with S-1 40 mg twice daily, followed by additional SOX for four more cycles. Hence, in D2-resected gastric cancer, both adjuvant chemotherapy and chemoradiotherapy are tolerated and beneficial in preventing relapse. For patients with involved lymph nodes, there may be an advantage of chemoradiotherapy over chemotherapy alone, a question being addressed in the ongoing ARTIST 2 trial.
Роль адъювантной лучевой терапии у пациентов, получающих периоперационную химиотерапию. To address the role of adjuvant chemoradiation in those who have received perioperative chemotherapy (the MAGIC, ACCORD, and 5- FU, leucovorin, oxaliplatin and docetaxel [FLOT4] trials), the Dutch Colorectal Cancer Group initiated the CRITICS trial.221 This study is a phase III prospective randomized trial that investigated whether chemoradiotherapy (45 Gy in 5 weeks with daily cisplatin and capecitabine) after preoperative chemotherapy (3 × epirubicin, cisplatin, and capecitabine) and adequate (D1+) gastrectomy leads to improved survival in comparison with postoperative chemotherapy alone (3 × epirubicin, cisplatin, and capecitabine). The results have only been reported in abstract form. Between 2007 and 2015, 788 patients from the Netherlands, Sweden, and Denmark were randomized. A total of 46% in the chemotherapy arm and 55% in the chemoradiation arm completed treatment according to protocol. The 5-year survival is 41.3% for chemotherapy and 40.9% for chemoradiation (not significant [NS]). Hence, it appears that the addition of postoperative chemoradiation did not provide improve survival among those receiving perioperative chemotherapy.
Предоперационная химиолучевая терапия. Although no phase III trials evaluating preoperative chemoradiation have focused specifically on gastric cancer, these patients have been included in a number of esophageal cancer trials.222 In these trials, the trimodality study arm demonstrated an improvement in OS when compared with the control arm of surgery alone. The U.S. GI Intergroup phase III trial (adenocarcinoma or squamous cell of esophagus or EGJ), compared surgery alone with 5-FU cisplatin–based preoperative chemoradiation. The trial closed prematurely because of low accrual, reported a median survival of 54 versus 22 months, and 5-year survival of 39% versus 16% (P = .008), with a significant advantage associated with the trimodality arm.222 In addition, a recent phase III randomized German trial compared preoperative chemotherapy alone (5-FU, leucovorin, and cisplatin) versus the same regimen followed by low-dose radiation therapy (30 Gy) with concurrent cisplatin and etoposide in patients with adenocarcinoma of the lower esophagus or gastric cardia. Although the trial was closed early because of poor accrual (126 patients), patients receiving radiation therapy had significantly higher pathologic complete response rates (2% versus 16%, P = .03) and trend toward improved survival (3-year survival, 47% versus 28%; P = .07).223 The CROSS trial224 compared surgery alone with preoperative chemoradiation carboplatin and paclitaxel for 5 weeks and concurrent radiotherapy (41.4 Gy) for patients with esophageal or EGJ carcinomas. Focusing on those with adenocarcinoma, with a median follow-up for surviving patients of 84.1 months, median OS was 43.2 months (24.9 to 61.4) in the neoadjuvant chemoradiotherapy plus surgery group, and 27.1 months (13.0 to 41.2) in the surgery alone group (HR, 0.73; 95% CI, 0.55 to 0.98; log-rank P = .038).225
Several small studies of preoperative chemoradiation data for patients with exclusively gastric cancer have demonstrated high rates of partial and complete pathologic response, which correlated with OS. Among 34 patients, induction chemotherapy of 5-FU, leucovorin, and cisplatin, followed by 45 Gy of radiation therapy, achieved 36% pathologic complete and an additional 29% partial responses. Median survival time was 64 months for patients with pathologic complete response and 12.6 months for patients with pathologic partial response.226 A subsequent trial of 41 patients with operable gastric cancer received two cycles of continuous 5-FU, paclitaxel, and cisplatin followed by 45 Gy of radiation therapy with concurrent 5-FU and paclitaxel. Pathologic complete response was seen in 20% and pathologic partial response in 15% of patients.227 The Radiation Therapy Oncology Group (RTOG 9904) was a phase II study of 49 patients undergoing induction 5-FU, leucovorin, and cisplatin followed by concurrent radiation therapy at 45 Gy, and infusional 5-FU and paclitaxel. The pathologic complete response rate was 26%. At 1 year, more patients with tumors exhibiting a pathologic complete response (89%) were alive than patients with tumors having less favorable pathologic treatment response (66%).260
A definitive answer to the role of preoperative chemoradiation will hopefully be provided by the TOPGEAR intergroup trial. Patients with resectable adenocarcinoma of the stomach or gastroesophageal junction will be randomized to receive either perioperative chemotherapy alone (three preoperative and three postoperative cycles of ECF) or perioperative chemotherapy plus preoperative chemoradiation. In the chemoradiation arm, patients receive two cycles of ECF plus chemoradiation prior to surgery, and then following surgery, three further cycles of ECF are given. Accrual is expected to be completed in late 2019; however, results have been published of a planned interim analysis of the first 120 patients.228 Compliance was similar in both arms, and better for pre- than postoperative therapy: the proportion of patients who received all cycles of preoperative chemotherapy was 93% (ECF group) and 98% (chemoradiation group), whereas 65% and 53%, respectively, received all cycles of postoperative chemotherapy. The proportion of patients proceeding to surgery was 90% (ECF group) and 85% (chemoradiation group). Grade 3 or higher surgical complications occurred in 22% of patients in both groups. Furthermore, grade 3 or higher gastrointestinal toxicity occurred in 32% (ECF group) and 30% (chemoradiation group) of patients, whereas hematologic toxicity occurred in 50% and 52% of patients, respectively. These preliminary results demonstrate that preoperative chemoradiation can be safely delivered to the vast majority of patients without a significant increase in treatment toxicity or surgical morbidity.
Периоперационная и неоадъювантная химиотерапия. Perioperative (pre- and postoperative) and neoadjuvant chemotherapy are attractive concepts in gastric cancer because many patients have locally advanced tumors at diagnosis, particularly in Western countries. There are two goals of perioperative treatment: to increase the likelihood of an R0 resection and treat micrometastatic disease early. After gastric resection, many patients have a prolonged recovery, delaying initiation of adjuvant therapy. Phase II trials involving either purely preoperative or perioperative treatment demonstrated that there was no increase in anticipated surgical morbidity or mortality when compared to controls.229,230 Evaluating efficacy at the primary site is difficult in gastric cancer, both EUS and CT have been shown to be inaccurate in restaging patients following neoadjuvant chemotherapy.231 FDG-PET imaging has been studied in patients with gastric cancer as a marker of response. Several studies have correlated changes in SUV uptake with pathologic response following neoadjuvant chemotherapy.232 Furthermore, a small recent study suggested that changing chemotherapy regimens in PET nonresponding patients may improve outcomes.233 However as previously noted, approximately 20% to 25% of patients with gastric cancer will not have an informative PET scan at presentation.
After phase II studies demonstrated safety and suggested efficacy, several perioperative chemotherapy phase III trials were conducted (see Table 53.5). The British MRC234 performed a well-designed phase III trial comparing surgery alone with surgery and perioperative chemotherapy in patients with gastroesophageal junction and gastric cancers (the MAGIC trial). All patients had potentially resectable disease prior to entrance into the study. Patients assigned to perioperative chemotherapy were treated with the ECF regimen. Chemotherapy was given both before and after surgery. A total of 503 patients were entered into the study; three-quarters had gastric cancer and one-quarter had gastroesophageal junction or lower esophageal adenocarcinomas. The ECF chemotherapy was well tolerated, with no increase in surgical morbidity or mortality. There was a shift to an earlier stage overall in patients receiving perioperative chemotherapy as well as an improved R0 resection rate. With a median follow-up of 4 years, there was a significant improvement in both DFS and OS for patients receiving perioperative chemotherapy: 5-year survival rate was 36% for those receiving perioperative chemotherapy and 23% for those receiving surgery alone (HR, 0.75; 95% CI, 0.6 to 0.9; P = .009). Hence, perioperative ECF chemotherapy improves outcome for patients with resectable gastric cancer without increasing operative morbidity or mortality. This important trial demonstrated the advantage of systemic treatment plus surgery when compared with operation alone.
The ACCORD 07-FFCD 9703 study, performed in France, investigated perioperative CF versus surgery alone reported similar results.235 Three-quarters of the patients had adenocarcinoma of the lower esophagus/gastroesophageal junction, and only a quarter had gastric cancer. Approximately half the patients receiving preoperative chemotherapy also received postoperative treatment using the same regimen. The results were similar to those of the MAGIC trial, with 5-year OS being 24% for operation alone versus 38% for those who received perioperative chemotherapy (P = .02); the corresponding 5-year DFS rates were 34% and 19%, respectively. This trial was prematurely terminated due to poor accrual. The results of the ACCORD 07 trial support the results of the MAGIC study.
Encouraging results of the FLOT4 randomized trial investigating the role of combined docetaxel-oxaliplatin have been reported in abstract form.236 Eligible patients with resectable gastric cancer of stage at least T2 and/or node positive were randomized to either three preoperative and three postoperative 3-week cycles of ECF/ECX (epirubicin 50 mg/m2, cisplatin 60 mg/m2, both day 1, and 5-FU 200 mg/m2 as continuous infusion or capecitabine 1,250 mg/m2 orally on days 1 to 21) or four preoperative and four postoperative 2-week cycles of FLOT (docetaxel 50 mg/m2, oxaliplatin 85 mg/m2, leucovorin 200 mg/m2, and 5-FU 2,600 mg/m2 as 24-hour infusion, all on day 1). Pathologic complete regression was 16% versus 6% in the FLOT versus ECF/ECX arms, respectively (P = .02). The FLOT regimen appeared better tolerated, with 44 of 111 (40%) patients in the ECF/ECX group and 30 of 119 (25%) patients in the FLOT group having at least one serious adverse event. With a median follow-up of 43 months, FLOT demonstrated an improved OS (50 versus 35 months for FLOT versus ECF/ECX, respectively; HR, 0.77; P = .012). Three-year OS rate was 57% with FLOT versus 48% with ECF/ECX. Of note, a similar percentage of patients were able to complete preoperative chemotherapy treatment in both arms (90% to 91%); however, a higher percentage in the FLOT arm completed postoperative treatment (50% versus 37%).
Based on the success of the trastuzumab for gastric cancer (ToGA) trial that demonstrated the efficacy of trastuzumab in HER2-expressing metastatic gastric cancer,237 the INNOVATIVE trial is comparing perioperative ECF alone with two experimental arms: (1) ECF combined with trastuzumab and (2) ECF combined with trastuzumab and pertuzumab.238
Резюме по периоперационной химиотерапии. To summarize, two well-conducted randomized studies (MAGIC, ACCORD 07) have established the role of perioperative systemic chemotherapy in gastric cancer versus surgery alone. Only approximately one-third of patients in these studies underwent D2 lymph node dissection; it is unclear the extent of impact of lymph node dissection on the results. Subsequently, a more recent study has demonstrated the superiority of the FLOT perioperative regimen. The best strategy to pursue—that is, whether to give systemic therapy first followed by operation or to proceed directly to operation followed by systemic treatment plus or minus radiation given before or after surgery—has yet to be determined.
Технические вопросы, связанные с лечением
The D2 subtotal gastrectomy commences with mobilization of the greater omentum from the transverse colon. After the omentum is mobilized, the anterior peritoneal leaf of the transverse mesocolon is incised along the lower border of the colon, and a plane is developed down to the head of the pancreas. The mesenteric lymph nodes (station 14) can be removed with the peritoneal surface of the bursa omentalis. The infrapyloric lymph nodes (station 6) are dissected, and the origins of the right gastroepiploic artery and vein are ligated. With a combination of blunt and sharp dissection, the plane of dissection continues on to the anterior surface of the pancreas, extending to the level of the common hepatic and splenic arteries. This maneuver can be tedious, but it theoretically provides additional protection against serosal spread of tumor to the local peritoneal surface. The suprapyloric lymph nodes (station 5) are then removed, and the right gastric artery is ligated. At this point, the duodenum is divided distal to the pylorus. The stomach and omentum are then reflected cephalad. The gastrohepatic ligament is divided close to the liver up to the gastroesophageal junction. Dissection is then continued along the hepatic artery removing all lymphatic tissues (station 8) toward the celiac axis. Once near the celiac axis, the lymph node–bearing tissue (station 9) is dissected until the left gastric artery is visualized and can be divided at its celiac origin removing lymphatic tissue at its origin (station 7). The proximal peritoneal attachments of the stomach and distal esophagus can then be incised, and the proximal extent of resection is defined. The pericardial lymph nodes (stations 1 and 2) can be dissected. For tumors of the mid- and proximal stomach, dissection of the lymph nodes along the splenic artery (station 11) and splenic hilum (station 10) is important. This technique is not indicated for antral tumors, given the low rate of splenic hilar nodal metastases seen with tumors in this anatomic location. In antral tumors, mobilization of the duodenum and pancreatic head facilitates removal of hepatoduodenal ligament lymph nodes (station 12) and posterior pancreatic nodes (station 13). The stomach is then divided 5 cm proximal to the tumor, which dictates the extent of gastric resection (including lesser curvature lymph nodes (station 3) and epiploic lymph nodes (station 4). Despite the fact that the entire blood supply of the stomach has been interrupted, a cuff of proximal stomach invariably shows good vascularization from the feeding distal esophageal arcade. When feasible, most surgeons prefer to anastomose jejunum to stomach rather than to esophagus because of the technical ease and excellent healing seen with gastrojejunal anastomosis. Reconstruction using a variety of techniques has been described and is a matter of personal choice.
Назогастральный дренаж после гастрэктомии
The Italian Total Gastrectomy Study Group reported on the largest RCT comparing total gastrectomy with Roux- en-Y with and without nasogastric tube (n = 237). There were no differences in overall morbidity, leak rate, hospital stay, and time to diet. Other authors confirmed that nasogastric tube is not necessary after gastrectomy.
Внутрибрюшинные дренажи после гастрэктомии
As with other pathologies, two RCTs concluded that drains after gastrectomy are generally not indicated and in certain situations can increase significantly operative morbidity.241,242
Реконструкция после гастрэктомии
Continuity of the gastrointestinal tract may be achieved in a variety of techniques. Following total gastrectomy, Roux-en-Y esophagojejunostomy is standard. Iivonen et al.243 compared Roux-en-Y with and without pouch. They randomized 48 patients and found significantly less dumping syndrome and early satiety but with no differences at 15 months of follow-up. Fein et al.244 reported on 138 patients randomized in a similar fashion; they found similar quality of life at 1 year but significantly improved quality of life at 3-, 4-, and 5-year follow-up. It seems that reconstruction with pouch has long-term advantages and may be recommended as the standard reconstruction after total gastrectomy. Following distal-subtotal gastrectomy, anastomosis between the duodenum and the gastric stump (Bilroth I) is popular mainly in Korea. Single anastomosis gastrojejunostomy (Bilroth II) is a technically easy option or Roux-en-Y gastric reconstruction may be performed. Multiple variations were described including the passage of the jejunum in an ante- or retrocolic fashion, site of anastomosis to the gastric stump (anterior wall, posterior wall, or to the resection line), and technique (hand-sewn versus stapled).
Ionizing radiation is a local modality that kills cancer cells through the induction of DNA damage. Challenges to the correct delivery of radiation in gastric cancer include the poor visualization of gastric tumors on preoperative imaging; difficulty in the interpretation of postoperative imaging; and organ movement within the abdomen as a consequence of respiration, gastric filling, peristalsis, and stance.
When reviewing the literature it is important to appreciate that radiation techniques for abdominal tumors have developed substantially over the previous three decades: from two-dimensional simulations and consequent treatment plans based on simple anteroposterior-posteroanterior (AP-PA) radiation fields used in the 1980s and early 1990s, through three-dimensional “conformal” treatment planning247 at the turn of the 21st century that typically utilized four radiation fields, to the complex intensity-modulated radiation therapy (IMRT) and volumetric modulated arc therapy (VMAT) plans248 commonly used today that utilize a very large number of beam angles, combined with three-dimensional imaging performed at time of treatment. Hence, although both the INT 0114215 (accrued 1991 to 1998) and CRITICS trials249 (commenced accrual in 2007) applied postoperative radiation to a similar dose, the techniques used and the exposure of the normal organs to radiation was likely very different. The overall aim of the radiation remains the same, but new techniques have enabled the improved sparing of normal tissues, in particular the kidneys, liver, and uninvolved small bowel.
There are three indications for radiation in gastric cancer: perioperative, palliative, and oligometastatic disease. Surgical resection alone is associated with high levels of local recurrence; the aim of perioperative radiation therapy is to improve local control and consequently OS through the sterilization of residual disease, this is especially important for the 20% of gastrectomy patients for whom local–regional relapse is their sole area of disease. Chemoradiation is now standard, based on earlier studies that demonstrated the superiority of combined 5-FU–based chemoradiation over radiation alone, although at the cost of increased toxicity. Small daily fractions of 1.8 to 2 Gy to a total dose of 45 to 50 Gy are used to minimize small bowel toxicity. Well-described areas of local relapse following gastrectomy include the tumor bed, gastric remnant, duodenal stump, areas of anastomosis, and regional lymph nodes. The precise lymph node areas requiring irradiation depend on the location and stage of the primary tumor; nodal chains at risk include the lesser and greater curvature, celiac axis, pancreaticoduodenal, splenic, suprapancreatic, porta hepatis, and para-aortic to the level of mid-L3. In gastroesophageal tumors mediastinal irradiation should be considered, whereas in more distal cancers the portahepatic lymph nodes are at risk. Patterns of recurrence after D2 dissections are remarkably similar to those see with less radical surgery. The INT 0114 established a survival advantage for postoperative radiation therapy combined with 5-FU. More recent studies (CRITICS, ARTIST I) have demonstrated lower levels of efficacy. It is unclear if this is due to a more aggressive surgical approach (although the role of D2 lymph node dissections is controversial), more efficacious systemic treatments, or a change in tumor biology (increase in diffuse histology type, for which benefit of radiation therapy is less than for intestinal type).
D2 lymph node dissections are increasingly performed in Western countries, even though phase III British and Dutch multicenter trials did not demonstrate a survival advantage for the technique. As only limited lymph node dissections were performed in INT 0114, the efficacy of chemoradiation after D2 dissections has been questioned. In a large retrospective study from Seoul, postoperative chemoradiation improved OS after D2 dissections. Likewise, in the ARTIST trial, chemoradiation improved DFS after D2 dissection amongst those with involved lymph nodes.
Neoadjuvant chemoradiation approaches are established for esophageal and gastroesophageal cancers, based on the phase III Cross trial.225 The role of neoadjuvant chemoradiation for tumors of the mid- and distal stomach is an ongoing area of interest, with nonrandomized trials reporting rates of pathologic complete response of around 25%.259,260 A historical trial that randomized gastric cancer patients between neoadjuvant radiation followed by surgery versus surgery alone demonstrated that 40 Gy radiation was able to downstage the primary and improve OS; however, chemotherapy was not delivered within the trial.210 The currently accruing TOPGEAR trial will address the role of neoadjuvant radiotherapy in addition to perioperative chemotherapy in gastric cancer.228
An additional but less common technique is IORT, involving a single fraction of 10 to 28 Gy delivered at the time of resection.261 Potential advantages of IORT include the ability to direct the beam to an at-risk area identified at surgery and the ability to improve anatomy by simply moving bowel out of the radiation field. Disadvantages include the difficulty in documenting the extent of the treatment field and lengthened operating time. Level 1 evidence for the efficacy of IORT is absent, and widespread expertise lacking.
An important newly recognized indication for radiation is oligometastatic disease. Oligometastatic disease is generally defined as disease confined to no more than five sites throughout the body and is understood to be an intermediate state between a locally confined primary cancer and widespread disease.262 Oligometastatic disease is an evolving indication for stereotactic body radiation therapy (SBRT) and other local ablative modalities. SBRT involves the delivery of a very high ablative radiation dose to a small confined volume and is well suited to brain, lung, liver, and retroperitoneal metastases. Typically, SBRT is associated with minimal side effects, although the practitioner has to be careful to avoid the exposure of normal tissues to very high radiation doses; therefore, the technique is less suited to masses abutting small bowel.263 The majority of the oligometastatic literature refers to colon, lung, and renal carcinomas, with little discussion of gastric cancer. Local treatment of oligometastatic disease, whether by SBRT, surgery, or other ablative treatment, may be associated with an increased disease-free interval and a delay in the use of systemic treatments. Whether such approaches improve OS is unclear, although this hypothesis is being currently testing in a number of accruing phase III trials, including the German RENAISSANCE trial (NCT02578368).
In unresectable gastric cancer definitive chemoradiation has a reported 3-year OS rate of 23%.264 The palliative role of radiation therapy in advanced gastric cancer is discussed later in this chapter.
Лечение заболевания поздней стадии (стадия IV)
Лечение рака желудка поздней стадии: паллиативная системная химиотерапия
Химиотерапия против лучшего поддерживающего лечения
Patients with gastric cancer frequently present with symptomatic widespread disease with dismal prognosis. The aims of therapy are to improve OS, pain control, improve quality of life, and enable nutritional intake. A meta- analysis comparing systemic chemotherapy with best supportive care concluded that systemic therapy extends OS by approximately 6.7 months more than best supportive care (HR, 0.63)265; median survival was improved from 4.3 months for best supportive care to approximately 11 months for chemotherapy. Note that the median survival for patients receiving chemotherapy is consistent with several more recent trials. A meta-analysis has likewise provided evidence to support second-line chemotherapy in advanced gastric cancer.266 A total of 410 patients were eligible for analysis, of whom 150 received docetaxel chemotherapy and 81 received irinotecan chemotherapy. A significant reduction in the risk of death (HR, 0.64; P < .0001) was observed with salvage chemotherapy. When the analysis was restricted to irinotecan or docetaxel, there was still significant reduction in the risk of death with each chemotherapeutic agent. The HR was 0.55 (P = .0004) for irinotecan and 0.71 (P = .004) for docetaxel.
Химиотерапия единичным агентом
A number of diverse agents have demonstrated at least modest activity in the treatment of gastric cancer and which are routinely used in clinical practice options (Table 53.6). Drugs with little or no activity, especially if they were evaluated prior to 2000, are not included in this table.
The antimetabolite 5-FU is the most extensively studied single agent in gastric cancer, using a variety of intravenous schedules: once weekly and daily for 2 to 5 consecutive days. Studies from the 1990s suggest overall response rates (ORRs) of 10% to 20%, with a median duration of response, or time to progression (TTP), of approximately 4 months. The major toxicities reported in gastric cancer for 5-FU are mucositis, diarrhea, or mild myelosuppression. Because continuous intravenous infusion schedules can be cumbersome, oral analogs of 5-FU have been studied in gastric cancer. Three oral drugs of this class have been studied in gastric cancer. These are tegafur and uracil (UFT), S-1 (tegafur and two modulators, 5-chloro-2,4-dihydroxypyridine, and potassium oxonate), and capecitabine (Xeloda, Hoffmann-La Roche, Basel, Switzerland). The data for these agents are also shown in Table 53.6. S-1 has been most extensively studied in Japan. Although a response rate to single-agent S-1 of 44% to 54% was reported in Japanese patients, the response rate among European patients was substantially lower. Like capecitabine, S-1 is now undergoing study in combination with other agents, particularly cisplatin. UFT, which combines tegafur and uracil, elicited a response rate of 28% in Japanese patients with gastric cancer and a response rate of 16% in European patients when combined with leucovorin (European Organisation for Research and Treatment of Cancer [EORTC] study).267 Similar activity is seen with capecitabine as with other oral fluorinated pyrimidines.
Таблица 53.6. Активность селективных единичных агентов в раке желудка поздних стадий
|Препарат||Величина ответа (%)|
UFT, tegafur and uracil; S-1, tegafur and two modulators, 5-chloro-2, 4-dihydroxypyridine, and potassium oxonate.
Cisplatin was studied in the 1980s, in both previously treated and untreated patients, and a response rate of approximately 15% was reported. The major toxicities for cisplatin are nausea and vomiting, peripheral neuropathy, ototoxicity, and nephropathy. The development of efficacious antiemetics has significantly improved control of nausea and vomiting. An analog of cisplatin, carboplatin, has been less well studied in gastric cancer; it appears to have less activity in this disease, as compared to other epithelial malignancies. Oxaliplatin, a diamino cyclohexane extensively used in the treatment of colorectal cancer, has been included as part of combination chemotherapy for gastric cancer. A third class of cytotoxic agents with activity in gastric cancer is the taxanes. Both paclitaxel and docetaxel have been studied as single agents in gastroesophageal cancers. Docetaxel has been more extensively studied than paclitaxel, with an ORR of 19% as a single agent.268 The major toxicities are neutropenia, alopecia, and edema. Allergic reactions are seen in about 25% of patients. The most common dosing schedule for docetaxel is 100 mg/m2 every 3 weeks. The median TTP while on docetaxel therapy was 6 months. A schedule using lower doses given once weekly has also been studied with similar activity. On the basis of a large randomized study comparing CF to docetaxel-cisplatin–5-FU (DCF), docetaxel was approved by the U.S. Food and Drug Administration (FDA) for the treatment of advanced gastric cancer. Paclitaxel has also been studied in gastric cancer, although in smaller numbers of patients, and has a similar degree of cytotoxic activity.
A fourth class of active agent is represented by irinotecan. It has been studied both as a single agent and in combination with other cytotoxic agents. When used alone, response rates of 15% to 25% have been reported in both previously treated and untreated patients with advanced gastric cancer. The major toxicities of irinotecan are myelosuppression and diarrhea.
Anthracyclines also have activity in gastric cancer. Single-agent data from the 1960s and 1970s show a response rate for doxorubicin of 17%, and for epirubicin, a similar response rate of approximately 19%.
Единичный агент против комбинированной химиотерапии
The potential advantage of giving combination chemotherapy versus single-agent chemotherapy has been evaluated by Wagner et al.269 in an update of their original Cochrane review.265 Based on trials performed since the year 2000, they found that combination chemotherapy provided a modest but statistically significant survival advantage when compared to single-agent chemotherapy (11.6 versus 10.5 months; HR, 0.84; 95% CI, 0.79 to 0.89). A secondary analysis for response rate (39% versus 23%) and for TTP also favored combination chemotherapy. Toxicity is higher when several agents are given together, although this was not statistically significant. Treatment-related mortality was only slightly higher (1.1%) for patients receiving combination chemotherapy versus 0.5% when single-agent chemotherapy was used.
The role of anthracyclines as part of combination chemotherapy has been analyzed. Three studies with a total of 500 patients were included: Anthracyclines in a CF combination had a modest survival advantage over CF alone (HR, 0.77; 95% CI, 0.62 to 0.95).269 A similar advantage to anthracyclines in combination was found when 5-FU–anthracycline combinations without cisplatin were studied. In contrast to anthracyclines, there was a more modest, albeit not statistically significant, benefit for irinotecan-containing combinations. There was a modest improvement in OS for docetaxel-containing regimens, but this did not reach statistical significance. The response rate as a secondary objective was 36% for docetaxel-containing regimens versus 31% for non–docetaxel- containing regimens (not statistically significant). Oral fluoropyrimidines when compared to intravenous fluoropyrimidine therapy also showed no significant difference in median OS. The meta-analysis is in keeping with the results of the REAL-2 trial, which indicated noninferiority for oral capecitabine when compared to intravenous 5-FU. Similarly, oxaliplatin regimens were compared to cisplatin-containing regimens with modest superiority to oxaliplatin.
In summary, there are five classes of cytotoxic chemotherapy agents in which single agents have modest activity in gastric cancer. The response rates range from 10% to 25%, and the median duration of response is relatively short (4 to 6 months). As a result of the single-agent trials, 5-FU or capecitabine (or other oral fluoropyrimidines); cisplatin or oxaliplatin; docetaxel; and less commonly, paclitaxel, epirubicin, and irinotecan are the major components of conventional combination cytotoxic systemic chemotherapy regimens.
Цисплатин-фторурацил. One of the most widely used combination chemotherapy regimens in gastric cancer, is the two-drug combination of CF; several phase III randomized trials have used CF as the control arm. This allowed an opportunity for an evaluation of the efficacy of this combination in patients with advanced incurable gastric cancer, in terms of response rate, PFS, and OS, using currently accepted criteria for efficacy and toxicity of treatment. Table 53.7 shows the data from six studies in which CF was the control arm. The doses of cisplatin used were 80 to 100 mg/m2 per course. 5-FU was given as a continuous 24-hour infusion from days 1 to 5 at a dose of 800 to 1,000 mg/m2/day. Cycles were usually given on an every-28-day basis. Response rates, PFS, and OS were similar across the trials. Major objective tumor regression was reported in 20% to 30% of patients; complete clinical remission was very uncommon. The median TTP or PFS ranged from 3.7 months to 4.1 months, with median survival ranging from 7.2 months to 8.6 months. Two-year survival was between 7% and 10%.
In summary, there is consistent data for the efficacy (and toxicity) of the two-drug combination CF, and the meta-analysis performed by Wagner et al.269 supports the use of combination over single-agent chemotherapy.
Although type and incidence of treatment-related toxicity is consistent across most CF trials and is generally tolerable, it can be severe on occasion. For example, in the EORTC trial, grade 3 or 4 neutropenia was seen in approximately one-third of patients; one-quarter of patients had grade 3 or 4 nausea or vomiting. Similarly, in the more recent TAX325 trial, overall grade 3 or 4 toxicity was seen in 75% of patients receiving CF; in the FLAGS trial, treatment-related mortality occurred in 4.9% of patients receiving CF. Some toxicity may be ameliorated by improved supportive care. For example, newer antiemetics such as aprepitant should improve control of severe nausea and vomiting. More widespread use of supportive cytokine agents may decrease the incidence of neutropenic fever. Nonetheless, it should be recognized that CF, using the doses and schedules described previously, is associated with substantial toxicity in some patients.
The use of oral fluoropyrimidines in place of intravenous 5-FU has been studied in several phase III trials, including that of Kang et al.270 described earlier, the REAL-2 trial, and the FLAGS trial comparing CF to cisplatin–S-1. In the FLAGS trial, 1,029 patients received either cisplatin 100 mg/m2 and 5-FU 1,000 mg/m2 as a continuous 5-day infusion or a slightly lower dose of cisplatin plus oral S-1.271 Median OS was 8.6 months for patients receiving cisplatin plus S-1 versus 7.9 months in the CF arm, with less toxicity for the cisplatin–S-1 combination. These three trials indicate that oral fluoropyrimidine when given with a platinum compound is not inferior to intravenous 5-FU plus cisplatin.
Доцетаксел, цисплатин и фторурацил. TAX325 was a large randomized trial that compared DCF (221 analyzable patients) to CF (224 patients) in untreated patients with advanced gastric cancer.272 The primary end point of the study was TTP. The two arms of the study were well balanced for prognostic factors, including weight loss, performance status, and extent of disease. The median TTP was 3.7 months for patients receiving CF and 5.6 months for those receiving DCF (HR, 1.47; P = .0004). As a secondary end point, survival was also modestly increased from 8.6 months for CF to 9.2 months for DCF. The 2-year survival rate, however, was increased greater than twofold in the DCF treatment arm (2-year OS, 8.8% for CF and 18.4% for DCF). Another measure of efficacy favoring DCF was tumor response to treatment (37% for DCF and 25% for CF). Although this study indicated an advantage to the three-drug combination of DCF, toxicity was also increased and was very substantial. A total of 81% of all patients receiving DCF had at least one grade 3 or 4 nonhematologic toxicity as well as substantially more hematologic toxicity. Of the patients receiving CF, 14% had neutropenic fever, as did 30% of patients receiving DCF. However, there was no difference in the treatment-related mortality rate for the two arms. This study led to the approval of docetaxel by the FDA for the treatment of gastric cancer when given in association with CF.
The very substantial toxicity seen with the DCF regimen, however, has led to concerns regarding its general use. A number of studies have been performed using modifications of DCF to develop a more tolerable regimen. Several strategies have been pursued, most of which involve using somewhat lower doses of docetaxel and 5-FU, or modifications in the schedule as to duration of 5-FU infusion or timing of the cisplatin dose. Various regimens, including docetaxel, have been evaluated in the phase II/III setting, indicating that modifications of the treatment schedule may decrease toxicity while maintaining treatment efficacy.
Таблица 53.7. Комбинированная химиотерапия при раке желудка поздних стадий: схемы, включающие цисплатин-фторурацил, используются в качестве контрольной группы в рандомизированных исследованиях
|Исследование||Препарат||Доза (mg/mL)||Режим (d)||Количество пациентов||RR (%)||Median TTP/PFS (mo)||Median Survival (mo)||2-летняя выживаемость (%)|
|Dank et al.||C||100||1||163||26||4.2||8.7||<10|
|Kang et al.||C||80||1||156||32||5.5||9.3||<10|
RR, recovery rate; TTP, time to progression; PFS, progression-free survival; EORTC, European Organisation for Research and Treatment of Cancer; C, cisplatin; F, fluorouracil; JCOG, Japan Clinical Oncology Group; FLAGS, Cisplatin/S-1 with Cisplatin/Infusional Fluorouracil in Advanced Gastric or Gastroesophageal Adenocarcinoma Study; E, epirubicin; REAL, Randomized Trial of EOC +/− Panitumumab for Advanced and Locally Advanced Esophagogastric Cancer.
Иринотекан плюс фторурацил-лейковорин. A phase III trial compared 5FU, leucovorin and irinotecan (FOLFIRI) with CF in the first-line setting; a total of 170 patients received irinotecan–5-FU, and 163 received CF. The primary end point was TTP. The analysis allowed for a noninferiority comparison between the two arms. The study was reasonably well balanced for the usual prognostic indicators; approximately 20% of patients had EGJ tumors. There was no significant difference in the major objective response rate (32% for irinotecan–5-FU and 26% for CF) or in median TTP (5 months for irinotecan–5-FU and 4.2 months for CF). Median OS was also similar between groups (9 months for irinotecan–5-FU and 8.7 months for CF). Time to treatment failure was 4 versus 3.4 months for irinotecan–5-FU and CF, respectively (P = .018). Irinotecan–5-FU was better in terms of toxic deaths (0.6% versus 3%), discontinuation for toxicity (10% versus 22%), neutropenia, thrombocytopenia, and stomatitis, but not diarrhea, than CF. In summary, the study demonstrated that irinotecan–5-FU was not inferior to CF and was somewhat less toxic.
Цисплатин плюс иринотекан. Cisplatin plus irinotecan produced encouraging response rates and tolerable toxicity in single-arm phase II studies, leading to a random-assignment phase II trial comparing irinotecan-cisplatin with the FOLFIRI regimen. The response rate and the TTP were higher for irinotecan–5-FU than for irinotecan- cisplatin.
Фторурацил-лейковорин-оксалиплатин. As is the case for irinotecan-containing regimens, oxaliplatin plus 5-FU is a standard practice option for patients with both metastatic and locally advanced colon cancer. In part because of this data, 5-FU–leucovorin-oxaliplatin (FOLFOX) regimens have also been studied in gastric cancer. The toxicity spectrum is similar to that seen in patients with colorectal cancer, with the dose-limiting toxicity of peripheral neuropathy (oxaliplatin). Myelosuppression, mucositis, and diarrhea typical for 5-FU regimens were noted as well. Several FOLFOX phase II studies have now been reported in gastric cancer. ORRs of approximately 50% were observed, with median TTP of 5 to 6 months and median OS ranging from 10 to 12 months.
Эпирубицин, цисплатин и фторурацил. English investigators have extensively studied the three-drug combination ECF. Two random-assignment phase III trials have compared the ECF with a non–cisplatin- containing combination (FAMTX) or with a mitomycin-cisplatin–5-FU (MCF) combination.279 In the first study, ECF was more effective than FAMTX in terms of both response rate and median OS (8.7 versus 6.1 months). Two-year survival was also superior for the ECF combination (14% versus 5%).280 In the second study, Ross et al.279 compared ECF with MCF. In this larger study, 574 patients were treated. The primary end point was 1-year survival. The objective ORRs were similar between the two arms (ECF 50% and MCF 55%). Toxicity was tolerable, although myelosuppression was greater for the experimental MCF arm. There was a slightly improved median duration of survival for ECF (9.4 versus 8.7 months) and for 1-year survival (40% for ECF and 32% for MCF). There was no significant difference in 2-year survival, which was approximately 15% for both arms.279 Several studies have demonstrated that a small percentage of patients with advanced unresectable gastric cancer actually survive 2 years. Data for the ECF regimen as the control arm of the REAL-2 trial are discussed subsequently.
Клиническое исследование REAL-2
Partly on the basis of these studies, a phase III trial comparing an oxaliplatin-based regimen with cisplatin- containing combinations was performed. Cunningham et al. in the REAL-2 trial studied 1,002 patients who were randomized to one of four treatment groups: a control arm of ECF and three investigational arms. The central question in this study was the following: Can capecitabine be substituted for 5-FU and/or oxaliplatin substituted for cisplatin? The four arms were ECF, epirubicin-oxaliplatin–5-FU, epirubicin- cisplatin-capecitabine, and epirubicin-oxaliplatin-capecitabine (EOX). The four regimens are shown in Table 53.8. Patients were stratified for performance status and extent of disease. The primary end point was in OS. The study was powered to show noninferiority for capecitabine compared with 5-FU and oxaliplatin compared with cisplatin. There were approximately 250 patients per arm. The study design was a two-by-two comparison. A total of 40% of patients had primary gastric cancer, and the remainder had either EGJ or esophageal cancers, with 10% of patients having squamous cell cancer of the esophagus. There was no difference in median OS between the arms (ECF 9.9 months, epirubicin-oxaliplatin–5-FU 9.3 months, epirubicin-cisplatin-capecitabine 9.9 months, and EOX 11.2 months). The 1-year OS was also similar and ranged from 38% to 47%, the best outcome evident with EOX and the lowest with the control arm of ECF. Regarding toxicity, compared with cisplatin, oxaliplatin was associated with less neutropenia, alopecia, renal toxicity, and thromboembolism but with slightly higher incidence of diarrhea and neuropathy. The toxic effects of 5-FU and capecitabine were similar. The authors concluded the oxaliplatin could be substituted for cisplatin, and capecitabine could be substituted for 5-FU in the palliative setting.
Таблица 53.8. REAL-2 режимы
|Epirubicin||50 mg/m2 IV||1||Каждые 3 недели|
|Cisplatin||60 mg/m2 IV||1|
|PVI 5-FU||200 mg/m2/db||1|
|Epirubicin||50 mg/m2 IV||1||Каждые 3 недели|
|Oxaliplatin||130 mg/m2 IV||1|
|PVI 5-FU||200 mg/m2/db||1|
|Epirubicin||50 mg/m2 IV||1||Каждые 3 недели|
|Cisplatin||60 mg/m2 IV||1|
|Epirubicin||50 mg/m2 IV||1||Каждые 3 недели|
|Oxaliplatin||130 mg/m2 IV||1|
a Planned treatment duration 24 weeks (eight cycles).
b PVI 5-FU delivered by central venous access catheter.
REAL, Randomized Trial of EOC +/− Panitumumab for Advanced and Locally Advanced Esophagogastric Cancer; ECF, epirubicin- cisplatin-fluorouracil; PVI, protracted venous-infusion; 5-FU, 5-fluorouracil; EOF, epirubicin-oxaliplatin–5-FU; IV, intravenously; ECX, epirubicin-cisplatin-capecitabine; BID, twice a day; EOX, epirubicin-oxaliplatin-capecitabine.
A modified FOLFOX-6 schedule was demonstrated to be equivalent to 5-FU–leucovorin-cisplatin (FLP).282 Although this randomized study did not demonstrate superiority for oxaliplatin- containing regimens, it does support the results of the REAL-2 study for noninferiority comparing oxaliplatin and cisplatin.
Furthermore, in keeping with the results of the REAL-2 study, capecitabine can be substituted for 5-FU as demonstrated by Kang et al.284 in a noninferiority randomized trial comparing capecitabine/cisplatin versus 5- FU/cisplatin.270
Therefore, oxaliplatin and capecitabine are suitable alternatives to cisplatin and 5-FU. In upper gastrointestinal tract malignancies, oxaliplatin, cisplatin, 5-FU, irinotecan, capecitabine, taxanes, and anthracyclines have at least modest single-agent activity.
Терапия второй линии
Second-line chemotherapy versus best supportive care has been demonstrated in randomized studies to improve OS.283,284 However, patients with gastric cancer often have numerous comorbidities and complications of their malignancy (i.e., failure to thrive with significant protein-calorie losses, peritoneal carcinomatosis with limited bowel function) that preclude the safe administration of second-line therapy.
In one study, previously treated patients were randomly assigned to best supportive care or to single-agent irinotecan plus best supportive care. Despite the small sample size (n = 40), the investigators observed a significant improvement in the HR for death (HR, 0.48) with the administration of irinotecan (P = .012).285 In a larger Korean study, 201 patients were randomized to second-line chemotherapy (either irinotecan or docetaxel) after progression on CF therapy. Chemotherapy improved median OS: 3.8 versus 5.3 months for best supportive care and chemotherapy, respectively.284 The COUGAR-02 trial (n = 168) randomized patients between best supportive care and docetaxel combined with best supportive care; those receiving active treatment had a survival advantage (median OS, 5.2 versus 3.6 months, P = .01). Docetaxel improved quality-of-life measures (dysphagia and abdominal pain) but was associated with a high incidence of grade 3 to 4 neutropenia, infection, and febrile neutropenia.286 Together, these studies definitely establish that patients with metastatic gastric cancer who have maintained their performance status should be considered for second-line palliative chemotherapy as a standard of practice. A randomized study has shown paclitaxel and irinotecan to be equivalent in the second-line setting (median survival, 8.4 to 9.5 months).287
Recent studies have investigated the role of combination chemotherapy in the second-line setting. Second-line irinotecan plus cisplatin has not been shown to be more effective than irinotecan alone in with advanced gastric cancer refractory to S-1 monotherapy.288 A recent systemic review and meta-analysis evaluated third-line therapy in gastric cancer compared with versus best supportive care.289 Therapy improved medial OS from 3.20 months to 4.80 months compared with best supportive care; however, the authors commented on the paucity of quality-of- life data.
Суперсемейство рецепторов эпидермального фактора роста: моноклональные антитела
Trastuzumab. Overexpression or amplification of HER2 (epidermal growth factor receptor 2 [EGFR]) occurs in approximately 20% of patients with gastric cancer; it varies with the subtype, being more common in intestinal- type tumors. A phase III study of trastuzumab plus chemotherapy versus chemotherapy alone was performed in patients with gastric cancer overexpressing HER2 in the first-line setting, the ToGA trial.290 Among 3,807 patients, 594 patients had HER2-positive gastric cancer. They were randomized to receive either CF or XP given every 3 weeks for six cycles or the same chemotherapy plus trastuzumab. The median OS was 13.8 months for patients receiving trastuzumab plus chemotherapy versus 11.1 months for those receiving chemotherapy alone (HR, 0.74; P = .0046). The most common adverse events in both groups were nausea (trastuzumab plus chemotherapy, 67%, versus chemotherapy alone, 63%), vomiting (147, 50%, versus 134, 46%), and neutropenia (53% versus 57%). Rates of overall grade 3 or 4 adverse events (68% versus 68%) and cardiac adverse events (6% versus 6%) did not differ between groups. The response rate was 47% for patients receiving trastuzumab plus chemotherapy versus 35% for those receiving chemotherapy alone.237 The ToGA trial used a HER2 scoring system similar to that used in breast cancer. HER2 was more likely to be positive in patients with EGJ tumors than in more distal tumors (33% versus 20%); patients with diffuse gastric cancer were much less likely to have a HER2-positive (6%) tumor. There is currently no data for second-line use of trastuzumab in gastric cancer.
Numerous targeted agents have failed to demonstrated efficacy in clinical trials despite initial excitement, including antibodies against EGFRs (cetuximab291,292 and panitumumab) and tyrosine kinase inhibitors including gefitinib, erlotinib, and lapatinib.293 For instance, a phase III study examined lapatinib in the second-line setting among Asian population patients with advanced gastric cancer who were HER2 positive by fluorescence in situ hybridization (FISH). A total of 261 patients were randomly assigned to receive either weekly paclitaxel or paclitaxel with lapatinib. The addition of lapatinib was not associated with a statistical improvement in OS (11.0 versus 8.9 months, P = .104).
Суперсемейство сосудистого эндотелиального фактора роста: моноклональные антитела
Bevacizumab. Bevacizumab is a humanized monoclonal antibody that binds the vascular endothelial growth factor ligand (VEGFA). In the AVAGAST multinational phase III trial comparing bevacizumab plus XP versus XP alone, 774 patients were randomly assigned to XP (n = 387) or XP/bevacizumab (n = 387).294 The study did not meet the primary end point of improving OS (12.1 months with XP/bevacizumab versus 10.1 months with XP, P = .1), but bevacizumab did demonstrate improvement in PFS (6.7 versus 5.3 months, P = .004) and ORRs (46.0% versus 37.4%, P = .03). In this study, non-Asian patients appeared to benefit more than Asian patients. Furthermore, patients with high baseline plasma VEGF-A appeared to benefit from bevacizumab therapy (HR, 0.72; 95% CI, 0.57 to 0.93), and similarly, patients with low baseline expression of neuropilin 1 also showed a trend toward improved OS with bevacizumab (HR, 0.75; 95% CI, 0.59 to 0.97).295 The AVATAR study was a phase III trial with the same treatment arms as the AVAGAST trial performed exclusively in China. In this trial, there was no difference in OS, PFS, or response rates between the arms.296
Суперсемейство сосудистого эндотелиального фактора роста: ингибиторы тирозинкиназы
Sunitinib is an oral inhibitor of VEGF receptors VEGFR1, VEGF2, and VEGF3, and platelet-derived growth factor receptor (PDGFR) α, PDGFR β, and c-Kit.
In a randomized phase II trial comparing docetaxel alone with docetaxel combined with sunitinib, sunitinib improved the response rate (41% versus 14%) but not TTP.297
Apatinib, a tyrosine kinase inhibitor that selectively inhibits VEGFR2, is active in advanced gastric cancer. An Asian phase III study randomized 267 patients who had progressed on at least two lines of therapy to apatinib (n = 181 patients) or placebo (n = 92). Patients assigned to apatinib experienced a longer median OS (6.5 versus 4.7 months; HR, 0.709; P = .0149).298
In addition, a second study has demonstrated efficacy of VEGFR2 inhibition as monotherapy in gastric cancer. Ramucirumab (IMC-1121B) is a fully human immunoglobulin G1 monoclonal antibody targeting VEGFR2. The Regard study was a placebo-controlled, double-blind, phase III international trial conducted in the second-line setting in patients with metastatic gastric or EGJ adenocarcinoma. Median OS was 5.2 months for ramucirumab and 3.8 months for placebo (HR, 0.776; 95% CI, 0.603 to 0.998; P = .0473).299
The RAINBOW study randomized 885 patients to ramucirumab in combination with paclitaxel versus paclitaxel alone in advanced gastric cancer in the second-line setting.300 OS was significantly longer in the ramucirumab plus paclitaxel group than in the placebo plus paclitaxel group (median, 9.6 versus 7.4 months; HR, 0.81; P = .017). Grade 3 or higher adverse events that occurred in >5% of patients in the ramucirumab plus paclitaxel group versus placebo plus paclitaxel included neutropenia (41% versus 19%), leucopenia (17% versus 7%), hypertension (14% versus 2%), fatigue (12% versus 5%), anemia (9% versus 10%), and abdominal pain (6% versus 3%). The incidence of grade 3 febrile neutropenia was low in both groups (3% versus 2%). The combination of ramucirumab with paclitaxel significantly increases OS compared with placebo plus paclitaxel and has established a new standard second-line treatment for patients with advanced gastric cancer.
Regorafenib is an oral multikinase inhibitor inhibiting angiogenic, stromal, and oncogenic pathways. This drug was examined in a random assignment phase II study versus placebo in the refractory setting and resulted in a significant improvement in PFS (2.6 months with regorafenib versus 0.9 months with placebo; HR, 0.40; P < .001).301 A phase III study is now ongoing (INTEGRATEII, NCT02773524). Cumulatively, these studies demonstrate a benefit of antiangiogenic therapy in gastric and gastroesophageal malignancies.
Ингибирование механистической мишени рапамицина (протеинкиназы)
Everolimus is an oral inhibitor of the mammalian target of rapamycin. Doi et al.302 reported a phase II trial testing everolimus in refractory metastatic gastric cancer. In 53 patients, the disease control rate was 56%, and the median PFS and OS were 2.7 and 10.1 months, respectively.302 Based on these encouraging results, a phase III study was performed comparing everolimus to best supportive care in the second-line setting. In this study, 656 patients were randomized in a 2:1 fashion to everolimus versus placebo. Median OS was similar in both arms, 5.4 versus 4.3 months (HR, 0.9; P = .1).
Ингибиторы поли (АДФ-рибоза) полимеразы
Olaparib is an oral inhibitor of poly (ADP-ribose) polymerase (PARP), which is now approved for BRCA-mutated ovarian and breast cancers. A phase II study initially demonstrated encouraging activity of olaparib when added to paclitaxel.304 A consequent large phase III trial, the GOLD study, compared olaparib plus paclitaxel versus placebo plus paclitaxel in the second-line setting.305 Two coprimary populations were assessed: the overall population of all patients and patients whose tumors were ATM-negative. OS did not differ between treatment groups in the overall patient population (8.8 months in the olaparib group versus 6.9 months in the placebo group) or in the ATM-negative population (12.0 versus 10.0 months). Hence, the GOLD study did not meet its primary objective of showing a significant improvement in OS with olaparib in the overall or ATM-negative population of Asian patients with advanced gastric cancer.
There is emerging evidence for the role of the immunotherapy in determining outcomes in gastric cancer. Checkpoint inhibitors restore immune system function and have demonstrated activity in multiple tumor types. These drugs were initially examined in the second- and third-line setting; subsequent studies are investigating the role of these agents in first-line metastatic and adjuvant treatment. There is ongoing uncertainly regarding use of PD-1 and PD-L1 expression as a predictive biomarker.
Keynote-012 was a multicenter phase Ib study to assess the safety and activity of pembrolizumab in PD-L1– positive recurrent or metastatic gastric cancer.306 Five (13%) patients had a total of six grade 3 or 4 treatment- related adverse events, consisting of two cases of grade 3 fatigue and one case each of grade 3 pemphigoid, grade 3 hypothyroidism, grade 3 peripheral sensory neuropathy, and grade 4 pneumonitis. Of the 36 evaluable patients, 8 patients had a partial response (22%), 5 patients had stable disease (14%), and there were no complete responses. For the purposes of the survival analysis, the population was split into two groups, within and outside of Asia. Median duration of response was 40 weeks in Asia, and not yet reached outside of Asia. Median OS was 11.4 months in the Asian population, and not yet reached in the rest of the world.
The CheckMate 032 study was a phase I/II study of nivolumab alone or with ipilimumab in advanced and metastatic gastric cancer that had progressed on chemotherapy, irrespective of PD-L1 status. The results have only been reported in abstract form.307 In this 42-patient subset, 62% of patients had gastroesophageal junction cancer, and 38% had gastric cancer. A total of 93% of patients had prior systemic treatment in the metastatic setting, 43% had two prior regimens, and 57% had three prior regimens. The ORR was 7.1%, and stable disease 31%, with an overall disease control rate of 38.1% in a heavily pretreated population. Median PFS was 1.49 months. Median OS was 8.5 months. OS rates at 6 and 12 months were 58.1% and 44.3%, respectively.
The KEYNOTE-059 study was a phase II multicohort study for patients with metastatic gastric adenocarcinoma; the results have only been reported in abstract form. Cohort 1 enrolled 259 patients who had received at least two prior lines of therapy, of whom 57% had PD-L1–positive tumors. Patients received pembrolizumab 200 mg alone every 3 weeks for up to 2 years. ORR was 12%, and median duration of response (DOR) was 14 months. The PFS 6-month rate was 15%, and the OS 6-month rate was 46%. In patients with PD- L1–positive tumors, ORR was 16%, median DOR was 14 months, 6-month PFS was 20%, and 6-month OS was 50%.
Cohort 2 enrolled 25 patients who received pembrolizumab and cisplatin combined with either 5-FU or capecitabine in the first-line setting. Confirmed ORR was 60% overall, 73% in PD-L1–positive, and 38% in PD- L1–negative tumors. Cohort 3 enrolled 31 patients with PD-L1–positive gastric cancers who received pembrolizumab alone in the first-line setting. Confirmed ORR was 26%.308
A number of trials are investigating the incorporation of immunotherapy in the first-line setting, in addition to cohorts 2 and 3 of KEYNOTE-059 discussed previously. The ATTRACTION-04 study, part 1, is a randomized, open-label trial to evaluate the feasibility of nivolumab in combination with oxaliplatin plus either S-1 or capecitabine. The results have only been reported in abstract form. A total of 40 patients were included in part 1: 21 patients were randomized to nivolumab and SOX and 19 to nivolumab and capecitabine plus oxaliplatin (Cape/Ox). Median duration of treatment was 7.03 months. Both treatments were well tolerated. Grade 3 to 4 treatment-related adverse events were reported in 23 (57.5%) patients. The ORR was 68.4%, and the disease control rate was 86.8%. Median PFS was not reached. A total of 18 (46.2%) patients remain on treatment at the time of the data cut off. There were no significant differences in activity and safety between the two treatments. Part 2 of the trial will accrue 650 chemo-naïve patients who will be randomized to receive chemotherapy (SOX or Cape/Ox, investigator’s choice) plus either nivolumab or placebo.309
The largest published study to date is ATTRACTION 2, a randomized, double-blind, placebo-controlled, phase III trial done at 49 clinical sites in Japan, South Korea, and Taiwan in patients with advanced gastric or gastroesophageal junction cancer who had been previously been treated with two or more chemotherapy regimens. Patients were randomly assigned (2:1) to receive nivolumab (n = 330) or placebo (n = 163). Median follow-up in surviving patients was 8.87 months in the nivolumab group and 8.59 months in the placebo group. Grade 3 or 4 treatment-related adverse events occurred in 34 of 330 (10%) patients who received nivolumab and 7 of 161 (10%) patients who received placebo; treatment-related adverse events led to death in 5 of 330 (2%) patients in the nivolumab group and 2 of 161 (1%) patients in the placebo group Median OS was 5.26 months in the nivolumab group and 4.14 months in the placebo group (P < .0001). Twelve-month OS rates were 26.2% with nivolumab and 10.9% with placebo.310 Checkpoint blockage has demonstrated efficacy in patients with solid tumors and mismatch repair deficiency including patients with gastric cancer.311 A total of 86 consecutive patients with at least one prior therapy were enrolled in a recently published study. Evidence of mismatch repair deficiency was assessed by either polymerase chain reaction or immunohistochemistry. Objective radiographic responses were observed in 53% of patients, and complete responses were achieved in 21% of patients.312 Likewise, in the KEYNOTE-059 study, 7 of the 174 tumors analyzed were found to be MSI-H; in this small subset ORR was 57% and median DOR was not reached. In CheckMate 032, an exploratory analysis evaluated ORR and OS by MSI status in patients with gastric cancer treated with nivolumab monotherapy. MSI status was centrally assessed using a polymerase chain reaction–based assay. MSI status was determined in 25 patients: 7 (28%) were MSI-H, and 18 (72%) were non–MSI-H. ORR was 29% in MSI-H, patients, 11% in non–MSI-H patients, and 9% in patients with unknown MSI (MSI-U). Disease control rate (DCR) was 71%, 28%, and 26%, respectively. Of the 7 responders, 3 were PD-L1–positive (≥1% tumor expression), 3 were PD-L1–negative (MSI-U, n=2; non–MSI-H, n=1), and 1 was not evaluable for PD-L1 assessment (MSI-H). Median OS was 14.75 months (1.51, not achieved [NA]) in MSI-H patients, 6.49 months (2.96, 12.42) in non–MSI-H patients, and 5.03 months (2.76, 16.16) in MSI-U patients.313 In summary, immunotherapy for gastric cancer is a promising new treatment strategy for a subset for patients with gastric cancer. Toxicity profiles are manageable and similar to that seen in other disease sites. FDA approval has been granted for pembrolizumab and nivolumab for mismatch repair deficiency gastric cancer. FDA approval has also been granted for pembrolizumab in PD-L1–positive refractory gastric cancer. Optimal patient selection has yet to be determined. The biomarker PD-L1 expression correlated with treatment efficacy in a subset of patients; however, additional biomarkers need to be defined as some PD-L1 nonexpressing tumors show response. Furthermore, there appear to be differential response based on geographic and genetic factors, with Asian patients responding less well.
Хирургия в лечении метастатического рака желудка
Given the recent improvements in systemic therapy for gastric cancer, the question whether resection of oligometastatic disease from gastric cancer can provide survival benefit remains unanswered.
Резекция печени: Kerkar et al. reviewed the published data reporting on liver resection for gastric cancer; 19 studies reported on 436 patients. The majority of the patients had synchronous isolated liver gastric metastases. Overall, the 1-, 3-, and 5-year survival rates were 62%, 30%, and 27%, respectively; 13% (48 of 358) were alive at 5 years, and in studies with more than 10 years of follow-up, 4% (48 of 358) survived for more than 10 years.315 Outcomes from recent national series from England demonstrated clear survival advantage for patients undergoing liver resection: 40% versus 9% at 5-year survival.316–319
Резекция легкого: Standard of care for patients with pulmonary gastric metastases is chemotherapy with a median survival of 6 months. Kemp et al.320 reviewed the published data reporting on lung resections for gastric cancer: 21 studies reported on 43 patients. A total of 82% of patients (34 of 43) had a solitary lesion. At a median follow-up of 23 months, 15 of 43 (35%) patients had no evidence of disease. The 5-year OS was 33%. More recently, Shiono et al.321 reported 28% 5-year survival after lung resection for gastric cancer metastases. Recently, Uramoto et al. demonstrated 30% 3-year survival after pulmonary resection for gastric metastases.322
Мультивисцеральная резекция при раке желудка: Mita et al.323 reported on 103 patients who underwent multivisceral resection for T4b gastric cancer. Postoperative mortality and morbidity were 1% and 38%, respectively. OS at 3 years was 48% and 14% for R0 and R1 resections, respectively.
HIPEC для рака желудка: The surgery branch of the National Institutes of Health (NIH)/NCI has conducted a limited-scale prospective RCT comparing gastrectomy, metastasectomy plus systemic therapy, and systemic therapy alone (the GYMSSA trial).325 The GYMSSA trial randomized 17 patients with metastatic gastric cancer to gastrectomy, cytoreductive surgery (CRS)/HIPEC plus FOLFOXIRI (GYMS arm), versus FOLFOXIRI alone (SA arm) to study OS. All patients underwent comprehensive staging including laparoscopy. OS in the CRS- HIPEC arm was 11.3 versus 4.3 months in the chemotherapy alone arm. All patients surviving beyond 12 months had initial peritoneal carcinomatosis index (PCI) ≤15. Another study randomized patients into CRS-HIPEC (OS, 11 months) versus CRS (OS, 6.5 months) arms.326 In a meta- analysis of randomized trials examining surgery plus intraperitoneal chemotherapy, improvement was demonstrated in 1-, 2-, and 3-year survival but no difference at 5- year survival.327 Although the results from Western randomized trials are awaited, CRS plus HIPEC studies from Asia demonstrated survival advantage. The authors of this chapter recommend considering CRS-HIPEC for highly selected group of patients.328–335
Gastric carcinomatosis occurs in 5% to 50% of patients undergoing surgery with curative intent. The median survival for such patients is 1.5 months to 3.1 months. Overall data are limited; however, several investigators reported on CRS plus HIPEC for gastric carcinomatosis—the median OS ranged from 6 to 21 months, and 5-year survival ranged from 6% to 16% with operative mortality of 2% to 7% mortality. In patients with optimal cytoreduction (completeness of cytoreduction [CCR0/1]) (no macroscopic or disease <5 mm), the 5-year survival was 16% to 30%. Complete cytoreduction was possible in only 44% to 51% of the patients. In 2008, the Fifth International Workshop on Peritoneal Surface Malignancy indicated that peritonectomy, intraoperative, and early postoperative HIPEC potentially can be a powerful therapy against gastric cancer peritoneal carcinomatosis.
Bidirectional chemotherapy utilizing intraperitoneal and systemic induction chemotherapy prior to CRS and HIPEC has been studied (retrospectively) in patients with peritoneal carcinomatosis of gastric origin undergoing treatment in a specialized peritoneal surface malignancy unit in Japan. A study of 194 patients with gastric carcinomatosis treated initially and responsive (response rate, 78%) to intraperitoneal docetaxel (20 mg/m2) and cisplatin (30 mg/m2) followed by four cycles of oral S-1 (60 mg/m2), followed by CRS/HIPEC, reported median OS of 16 months and 1-, 2-, and 5-year survival of 66%, 32%, and 11%, respectively.336 Operative morbidity and mortality were 24% and 4%, respectively. Response to bidirectional intraperitoneal and systemic chemotherapy, low tumor burden (peritoneal cancer index ≤6) and CCR0/1 were independently associated with improved OS on multivariate analysis.
Pressurized intraperitoneal aerosol chemotherapy (PIPAC) was first introduced by Marc-Andre Reymond for palliation or volume reduction of peritoneal metastasis. This is a simple technique based on laparoscopic injection of low-dose chemotherapy in patients with refractory ascites or high-volume peritoneal disease either for palliation or downstaging before CRS and HIPEC.337 PIPAC was shown in a small-scale retrospective study to be effective both for palliation and for volume reduction of peritoneal metastasis of gastric origin.338
Хирургия в паллиативном лечении
Because survival for patients with advanced gastric cancer is poor, any proposed operation could have a good chance of providing sustained symptomatic relief while minimizing the attendant morbidity and need for prolonged hospitalization. Ekbom and Gleysteen339 have reviewed the results of palliative resection versus intestinal bypass (gastrojejunostomy) in 75 patients with advanced gastric cancer. The most frequent symptoms for which patients underwent operation included pain, hemorrhage, nausea, dysphasia, or obstruction. Operative mortality was 25% for gastrojejunostomy, 20% for palliative partial or subtotal gastrectomy, and 27% for total or proximal palliative gastrectomy. The most common and often fatal complication was anastomotic leak. After gastrojejunostomy, 80% of patients had relief of symptoms for a mean of 5.9 months compared with palliative resection, which provided relief of symptoms in 88% of patients for a mean of 14.6 months. Although the duration of palliation was significantly longer after resection (P < .01), the selection criteria for resection versus bypass were not controlled, and some bias against performing a palliative resection in high-risk patients with more advanced disease may have occurred. Meijer et al.340 also reported on a retrospective analysis of 51 patients undergoing either palliative intestinal bypass or resection. In 20 of 26 (77%) patients undergoing resection, palliation was considered moderate to good with a mean survival of 9.5 months. After gastroenterostomy, some palliation was noted in 8 of 25 (30%) patients, and survival was 4.2 months. Butler et al.341 presented the results of total gastrectomy for palliation in 27 patients with advanced gastric cancer. Operative mortality was only 4%, whereas morbidity occurred in 48% of patients. Median survival was 15 months, with a survival rate of 38% at 2 years. This substantial survival rate at 2 years reflects that although all patients were symptomatic before surgery, only half had stage IV disease. Patients with linitis plastica present a very difficult therapeutic challenge. Resection may provide palliation of symptoms; however, survival after total gastrectomy is exceedingly poor, ranging from 3 months to 1 year.342–344
Bozzetti et al.345,346 reviewed the outcomes of 246 patients with advanced gastric cancer who underwent simple exploratory laparotomy alone, gastrointestinal bypass, or palliative resection at the National Cancer Institute of Milan. When survival was compared in patients with similar type and extent of disease, a consistent trend was seen for improved median OS with palliative resection in patients with local (4 versus 8 months) and distant spread of disease (3 versus 8 months). Boddie et al.347 reported similar results in 45 patients undergoing palliative resection at the MD Anderson Cancer Center for advanced gastric cancer. Operative mortality for resection was 22%. In 21 patients who had undergone a palliative bypass procedure, OS was significantly shorter than for those undergoing palliative gastric resection (P < .01).
In select patients with symptomatic advanced gastric cancer, resection of the primary disease appears to provide symptomatic relief with acceptable morbidity and mortality, even in the presence of macroscopic residual disease.348
Роль лучевой терапии в паллиативном лечении рака желудка
In the palliative setting, the principal indications for radiotherapy are gastric bleeding, pain, and dysphagia/obstruction. Generally, radiation is administered at a dose of 20 to 40 Gy as a fractionated schedule over 1 to 3 weeks, although there is also limited experience with a single 8-Gy treatment.349 Treatments are generally well tolerated, with the principal side effects being transient nausea, vomiting, and anorexia. Of patients receiving palliative radiotherapy alone, 15% have been reported to experience grade 3 to 4 toxicities, as opposed to 25% of those receiving chemoradiation.350 As detailed in the following text, treatment is remarkably effective; for many patients, symptom control is achieved for the majority of their remaining lives.
The largest experience is with gastric hemorrhage. Radiotherapy is effective at stopping bleeding in the majority of patients within 2 or 3 days of the initiation of treatment.349,351 A dose of 30 Gy over 2 weeks is typically used,351,352 although one study has suggested a benefit for slightly higher doses (a biologic effective dose of 50 Gy—an alpha-beta of 10, corresponding to 39 Gy in 13 fractions).353 Beyond this dose, there appears to be no additional benefit.349 One study that utilized lower radiation doses (the majority received a single fraction of 8 Gy) also reported a lower response rate of 50%.354
For pain relief and gastric obstruction, published experience is more limited. Radiation has been reported to relieve pain in approximately half of patients.349,355 Radiation has also been reported to be successful in relieving obstruction/dysphagia in 50% to 80% of patients.349,355,356 Aside from radiotherapy, these patients have other palliative options. Two small randomized trials have compared the effectiveness of laser recanalization alone, to laser recanalization combined with radiation therapy (either external beam or brachytherapy); both trials concluded that the addition of radiation meaningfully lengthened the time until dysphagia recurred.357,358 There is also evidence that radiotherapy is effective in reliving obstructed jaundice caused by gastric cancer metastases.
Рак желудка у пожилых
Gastric cancer in the United States is predominantly a disease of the elderly, with a median age of diagnosis of 68 years and 34.5% of patients aged 75 years or older.361 Conversely, the median age of subjects in three recent trials (ARTISTS, CRITICS, and MAGIC trial) ranged between 56 and 62 years. Furthermore, it is well recognized that clinical trial participants are generally healthier and have fewer comorbidities than age-matched members of the general population.362,363 Hence, the results of randomized trials cannot be simply extrapolated to the more elderly patients seen in the community.
Several studies have demonstrated that elderly patients tolerate surgery less well; for instance, in the Dutch D1D2 trial postoperative mortality was significantly higher in those older than the age of 70 years (overall risk, 3.55; P < .0001).122 Likewise, a German study demonstrated that 30-day mortality increased with age, being 0%, 1%, and 8% for age younger than 60 years, 60 to 75 years, and older than 75 years, respectively.
The tolerability of systemic chemotherapy appears to depend more on functional status than chronologic age. Furthermore, a multidimensional score system consisting of geriatric assessment variables, laboratory test values, and patient, tumor, and treatment characteristics has been shown to better predict risk of chemotherapy-induced toxicity than simple physician-rated performance status.365
Fit elderly patients appear to benefit equally from systemic chemotherapy. In the MAGIC trial, patients older than the age of 70 years appeared to benefit as much as those younger than the age of 60 years.234 In a large pooled analysis of 1,080 patients with esophageal-gastric cancer recruited to three different RCTs, investigators compared patients older and younger than the age of 70 years. There were no significant differences in the incidence of grade 3 or 4 toxicity between the two cohorts. Objective and symptomatic response rates, failure-free survival, and OS were not significantly different. In a multivariate analysis, IDPFs for survival were performance status and locally advanced disease, not age. The authors concluded that, compared with younger patients, patients aged 70 years or older obtained similar benefits from palliative chemotherapy with respect to symptomatic response, tumor regression, and survival, without increased toxicities.366
Regarding radiotherapy in the elderly, a subgroup analysis of the Southwest Oncology Group (SWOG)- directed INT 0116 based on age has yet to be published. Observational studies suggest that adjuvant chemoradiation is effective up to the age of 80 years.367 There is limited evidence that elderly patients are less tolerant of bowel irradiation than younger subjects.368 Population-based studies within the United States have demonstrated that older patients are less likely to receive adequate nodal evaluation and adjuvant radiotherapy.369
In conclusion, it does not appear that age itself is a prognostic factor in gastric cancer; however, elderly patients tolerate aggressive surgery poorly. Elderly patients appear to benefit from chemotherapy and chemoradiation to a similar degree as younger patients; however, those with comorbidities and poor performance status are at higher risk of experiencing side effects. The results of a comprehensive geriatric assessment incorporating functional and physiologic components is useful in determining the aggressiveness of treatment.
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