Adjuvant chemotherapy compared to the surgical control of curative resection of stomach cancer.
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\r\n\tIn this book Advanced application of radionuclides are introduced. New global trends on safe application of radionuclides in human life is elucidated.
Chronic thromboembolic pulmonary hypertension (CTEPH) is caused by a persistent obstruction of the pulmonary arteries after a pulmonary embolism (PE) that has not resolved despite 3 months of medical therapy with anticoagulants and is defined as a raised mean pulmonary artery pressure (at least 25 mmHg at rest), a pulmonary capillary wedge pressure of ≤ 15 mmHg and at least one (segmental) perfusion defect detected by lung scanning, multi‐detector computed tomographic angiography or pulmonary angiography [1, 2]. CTEPH is a form of pulmonary artery hypertension (PAH) characterized by the occlusion of the pulmonary arteries by organized fibrotic thrombi leading to increased pulmonary vascular resistance (PVR). The consequential effect is dyspnea, right heart failure and even death. CTEPH is classified as group IV according to the WHO classification of pulmonary hypertension [3]. Some patients may present symptoms and signs of CTEPH but no pulmonary hypertension; this presentation should be termed chronic thromboembolic disease, although the management of these patients does not differ to that of the classic CTEPH patients.
The most common cause of CTEPH is non‐resolving acute pulmonary embolism (PE) and can occur after one or multiple episodes. Occasionally, CTEPH may develop after in situ pulmonary artery thrombosis which could be associated with the inflammation of vessel walls [4].
CTEPH can be mistaken for PE; it is important to differentiate between these, in order to diagnose the chronic disease as early as possible. Once the diagnosis of CTEPH is made, careful patient selection in experienced centers is preferable in order to obtain the best results for these patients.
Because of its unique characteristics, CTEPH is the only form of PH that can be curable by pulmonary endarterectomy (PEA); although, this is a complicated surgery and not every patient may be fit to undergo such a procedure. The most benefited patients are those who present a proximal compromise [5].
CTEPH remains underdiagnosed and carries a poor prognosis. Medical and interventional treatment are options for patients that are not surgical candidates. In this chapter, the available information on the surgical treatment of CTEPH is summarized.
The first description of the CTEPH was made in 1928 by Dr Ljungdahl on two symptomatic patients with chronic obstruction of the pulmonary arteries who ultimately died of right heart failure [6]. The first successful embolectomies for recurrent pulmonary embolism were reported by Allison and colleagues in 1958 and by Snyder and colleagues in 1962 [7, 8]. Then, Cabrol et al. refined the technique using a lateral thoracotomy in order to obtain access to distal pulmonary branches [9]. In 1980, Daily et al. reported the use of cardiopulmonary bypass (CPB) and hypothermic circulatory arrest, allowing the reduction of severe back bleeding and improving the visualization of the pulmonary arteries during endarterectomy [10]. This is the current preferred technique.
The process of the disease typically occurs in the proximal pulmonary arteries from trunk to sublobar levels. The distal vasculature remains patent. This presentation is the basis for the surgical approach of CTEPH. The disease may develop from a single embolic episode with non‐resolution of large thrombi or from repeated thromboembolic episodes [11]. The remaining unobstructed pulmonary arteries are exposed to high flow and eventually high pressure. Then, proximal patent pulmonary arteries enlarge, and the distal arterial vasculature develops changes of pulmonary hypertension such as intimal proliferation and medial hypertrophy. The characteristic diagnostic finding of primary pulmonary hypertension, the plexiform lesion, is also observed in CTEPH [12]. The occlusive process is usually central, incipient and unresponsive to antithrombotic or anticoagulant therapy when the thrombi become fibrotic and endothelialized. The thrombotic material has well‐organized fibrous tissues, penetrating blood vessels, elastic fibers and no endothelial cells. The arterial layers demonstrate intimal and medial hyperplasia. Infarction of the lung tissue is rarely observed [2]. These microvascular changes explain why CTEPH is a progressive disease even in the absence of recurrent thromboembolic events.
The estimated prevalence of CTEPH after acute pulmonary embolism is 0.1–4% after 2 years [2, 13–16]. The median age at diagnosis is 63 years, and both genders are equally affected [17]. The risk of developing CTEPH is increased in patients with recurrent venous thromboembolism, echocardiographic signs of pulmonary hypertension at the initial presentation and large perfusion defects. Common risk factors for venous thromboembolism (factor V Leyden, factor II mutation) are not associated with the development of CTEPH except for the presence of antiphospholipid antibodies, which predispose patients to acute venous thromboembolism and CTEPH [1, 18–20]. Different disorders considered to be risk factors include inflammatory bowel disease, splenectomy, myeloproliferative disorders, chronic osteomyelitis and the presence of permanent central venous lines, pacemakers or ventriculoatrial shunts [20–23]. These disorders are associated with chronic inflammation, an increased risk of repeated bloodstream infection or both, which may contribute to the non‐resolution of thromboembolic material [1]. C‐reactive protein is also implicated in the development of CTEPH [24]. Infection of thrombotic material by blood-borne pathogens could predispose to the development of CTEPH, specially in patients with permanent central venous lines, pacemakers or ventriculoatrial shunts [25].
It is relatively infrequent to find a complete resolution of pulmonary embolism. If adequate anticoagulation therapy has been done, more than 50% of patients have residual perfusion defects 6 months after the diagnosis of pulmonary embolism [26]. However, the majority of these patients do not develop florid chronic pulmonary hypertension; in fact, patients presenting signs of pulmonary hypertension during an episode of acute pulmonary embolism are unlikely to develop CTEPH, and most of these patients recover a stable phase of right ventricular functions within 40 days [13]. Some patients, however, present persistent pulmonary hypertension and others develop pulmonary hypertension after a symptom‐free interval that can last from months to years [14]. Hemodynamic deterioration may be the result of recurrent thromboembolism or in situ pulmonary artery thrombosis. Without intervention, survival is compromised and proportional to the degree of pulmonary hypertension at the time of diagnosis [27, 28]. To remind, pulmonary hypertension is not a feature of acute pulmonary embolism since the right ventricle (RV) is incapable of generating high pressures in early stages. In that order, any patient presenting with acute pulmonary embolism and elevated pulmonary resistances may already have CTEPH. In a study, the 5‐year survival rate was 30% among patients with a mean pulmonary pressure > 40 mmHg at time of diagnosis, and it dropped dramatically to 10% among those with a mean pulmonary pressure > 50 mmHg [29]. In another study, a mean pulmonary artery pressure of 30 mmHg marked the threshold for poor prognosis [30].
In general, symptoms do not develop until months or years after the embolic event [2]. They occur as a result of right ventricular failure or pulmonary hypertension. Progressive dyspnea on exertion is the predominant symptom of CTEPH [11]. Additionally, patients might present with fatigue, substernal chest pain with exercise, pleuritic pain and hemoptysis [11, 31].
Relevant physical findings are related to right heart failure: jugular venous distention, ascites, hepatomegaly and peripheral edema. The right ventricle may be enlarged and palpable near the lower left sternal border. The pulmonic second sound is accentuated and split. A murmur of tricuspid regurgitation might be heard in severe right heart failure.
CTEPH should be considered in all patients who have an evident history of acute pulmonary embolism. Despite 25% of the patients diagnosed as having CTEPH, there are no documented acute pulmonary embolism events [32]. Thus, CTEPH should be suspected in any patient with otherwise unexplained pulmonary hypertension.
The chest radiograph may demonstrate right ventricle enlargement and the prominence of central pulmonary arteries. The ECG frequently shows RV hypertrophy with strain, right axis deviation, ST depression, T‐wave inversion in the anterior precordial leads and occasionally right bundle branch block [31]. Transthoracic echocardiography provides the initial objective evidence for the presence of PAH. Findings in chronic thromboembolic and other forms of PAH include the enlargement of right cardiac chambers, tricuspid regurgitation as a consequence from this enlargement, the flattening or paradoxical motion of the interventricular septum and impaired left ventricular diastolic filling not caused by primary left ventricular diastolic dysfunction or valvular heart disease [33, 34]. Pulmonary function studies are necessary to exclude restrictive or obstructive pulmonary parenchymal disease as the cause of PAH.
Ventilation‐perfusion scanning is the preferred diagnostic tool because of its high sensitivity and a negative predictive value of almost 100% [35]. In that order, CTEPH is practically ruled out if the scan is normal [35]. A lung perfusion scan showing at least one segmental or larger defect is suggestive of chronic vascular obstruction [2]. Often, the scan underestimates the severity of an obstructive disease [36, 37]. Perfusion defects can also occur in other disorders such as pulmonary veno‐occlusive disease, pulmonary vasculitis, fibrosing mediastinitis or malignant disease [38–40]. CT scanning and MRI of the chest are important diagnostic tools and are being used with increasing frequency [41, 42]. If imaging suggests the presence of CTEPH, patients should be evaluated with right‐heart catheterization to measure the right ventricle and pulmonary artery pressures and to evaluate the presence of shunting at the atrial or ventricular level. Pulmonary angiography is safe in patients with chronic pulmonary hypertension [2, 43]. Typical findings include dilated proximal pulmonary arteries, varying degrees of obstruction of lobar arteries, filling defects, web or bands or thrombosed vessels suggesting the presence of organized thrombi [44]. In order to avoid repeat procedures, angiography should be done in a center that assesses the patient’s suitability for surgery. A general screening after acute pulmonary embolism is not recommended, given the low risk of developing CTEPH after such an event [45–47]. Care must be taken, however, in patients who show symptoms after an episode of acute pulmonary embolism. Echocardiography is widely used when suspecting pulmonary hypertension. A diagnostic approach that combines an electrocardiogram with no signs of hypertrophy in the right ventricle and a normal natriuretic peptide (N‐terminal‐pro‐brain‐type fragment) has a negative predictive value of 99% for CTEPH [48].
Angioscopy is an alternative tool adjunct to angiography, CT or MRI when these modalities cannot establish the diagnosis properly [49].
Patients diagnosed with CTEPH should have life‐long anticoagulation, even those who underwent successful PEA. The target international normalized ratio is 2.0 to 3.0. The use of filters in the inferior vena cava remains controversial [50]. Currently, the use of these filters is indicated when therapeutic anticoagulation is not feasible or when recurrent venous thromboembolism occurred despite sufficient anticoagulation [51]. Prospective studies on this matter are warranted.
The most important criterion that determines whether a patient with CTEPH might be a candidate for PEA is the presence of surgically accessible lesions. PEA should be considered in symptomatic patients who have hemodynamic or ventilatory impairment at rest or with exercise [52]. The decision to proceed with PEA in patients with CTEPH is difficult based on their preoperative pulmonary hemodynamic profile and the anticipated improvement in these hemodynamics postoperatively [27]. The basis for this concern is that the elevated vascular resistance not only arises from central (surgically accessible) vessels but also from secondary, small vessels with arteriopathy [27]. A preoperative approach should differentiate these two components and anticipate the postoperative hemodynamic outcome. This important issue remains relatively subjective. There is a high correlation between the postoperative level of pulmonary vascular resistance (PVR) and mortality. In a study by Jamieson and colleagues including 500 consecutive operated patients with an overall mortality of 4.4%, 77% of deaths were related to residual high pulmonary artery pressures. Patients with a postoperative PVR > 500 dynes‐sec‐cm−5 had a mortality rate of 30.6% compared to 0.9% in patients with a postoperative PVR < 500 dynes‐sec‐cm−5 [53]. The majority of patients who undergo a PEA have a PVR > 300 dynes‐sec‐cm−5. Experienced centers report a range of preoperative PVR between 700 and 1100 dynes‐sec‐cm−5 [53–58]. Symptomatic patients at the lower end of these values include those with involvement limited to one pulmonary artery, those accustomed to a vigorous activity and those who live at high altitudes [52]. Operations should also be considered for patients with nearly normal pulmonary hemodynamics at rest but marked pulmonary hypertension induced by exercise. The only absolute contraindication to operation is the presence of severe underlying obstructive or restrictive lung diseases [52]. The most important risk factor for surgery is the presence of high pulmonary resistances without visible abnormalities by angiography [53]. Older patients and severe RV failure are associated with increased risk but do not preclude surgery.
This is the description of the current accepted and most widely used technique for PEA. Electroencephalographic recording is essential to ensure the absence of cerebral activity before circulatory arrest is induced. The patient\'s head is involved in a cooling jacket. Standard preparations for the establishment of cardiopulmonary bypass (CPB) are made. A median sternotomy is performed. Cannulas are inserted into the ascending aorta and both venae cavae, which are encircled with tapes. Immediately after CPB starts, cooling is initiated (including the head jacket and the cooling blanket). This could take 45 minutes to 1 hour [59]. A venting catheter is placed in the left atrium through the upper right pulmonary vein. If the patient\'s condition allows it, autologous whole blood is withdrawn for later use. The deficit can be replaced with a crystalloid solution. The aorta is clamped and cold blood cardioplegia is given. Additional myocardial protection could be done by subsequent infusions of cold cardioplegic solution, every 15 to 20 minutes. During the cooling period, mobilization of the right pulmonary artery from the ascending aorta is made as well as the mobilization of the superior vena cava. Also, methylprednisolone (7 mg/kg) and thiopental (10–15 mg/kg) are administered to favor the neuroprotective effect of hypothermia. Mannitol (0.3–0.4 mg/kg) and furosemide (100 mg) are infused to preserve the renal function. Once the core temperature has reached 12–14°C and the electroencephalogram becomes isoelectric, circulatory arrest is established [60]. Both encircling tapes of superior and inferior vena cava are secured to ensure complete drainage and to avoid air embolization into the venous cannulae during circulatory arrest. An incision is made in the right pulmonary artery between the aorta and the superior vena cava (Figure 1), extending the incision toward the right lower lobe artery, a few millimeters farther from the takeoff of the middle lobe artery (Figure 2). Using a sharp dissector can help establish an endarterectomy plane (Figure 3). The intima and a portion of the media are removed. Establishment of the correct plane is essential—too deep will result in artery perforation, too shallow will result in an inadequate endarterectomy [61]. When the adequate plane is achieved, the layer will dismount easily. The core of the thrombus is dissected in a circumferential manner (Figure 4) and removed from each subsegmental branch and from the pulmonary artery (Figure 5). Gentle traction with forceps is applied to the core as well as opposite force to the pulmonary wall that will facilitate the removal of the specimen (Figure 6). The remaining core is removed from the proximal portion of the right pulmonary artery (Figure 7). The arteriotomy is closed with a continuous 5–0 or 6–0 polypropylene suture (Figure 8). If needed, a pericardial patch can be used that is sutured into place with a continuous 6–0 polypropylene suture. The period of circulatory arrest ranges from 20 to 25 minutes. Cold blood is reperfused for 8–10 minutes between these intervals. As for the left side, the incision begins in the pulmonary trunk and extends onto the left pulmonary artery to the level of the pericardial reflection (Figure 9). Endarterectomy of the left side mirrors that of the right pulmonary artery. The core is removed from the upper lobe artery and each subsegmental branch. The artery is closed in a continuous fashion or with an autologous pericardial patch. CPB begins and rewarming of the patient is established. If any other defects are present, such as patent foramen ovale or atrial septal defect, these are corrected to prevent the right‐to‐left shunting. If additional procedures are required, they are made during rewarming [62]. Right ventricle remodeling occurs within a few days, so, any tricuspid regurgitation rarely needs repair or replacement [61, 62]. Deariation maneuvers from cardiac chambers are performed, CPB is discontinued and the procedure is completed in the usual fashion.
An approach to pulmonary artery. View from left side. Superior vena cava is completely mobilized and retracted laterally, and aorta is retracted medially. The incision on pulmonary artery is done between these two vessels.
Exposure of distal right pulmonary artery between aorta and superior vena cava. Dashed line indicates line of incision.
Endarterectomy plane is facilitated with a sharp dissector.
Circumferential isolation of the core of the thrombus and extraction from upper lobe and distal pulmonary artery.
Extraction of the core of the thrombus.
Separation of core from proximal pulmonary artery.
Complete extraction of core specimen.
Arteriotomy is closed with a continuous 5–0 or 6–0 polypropylene suture.
Incision in left pulmonary artery (dashed line) begins in the pulmonary trunk and extends onto the left pulmonary artery.
An FiO2, high enough to maintain SaO2 > 95%, during mechanical ventilation, is preferred. PaCO2 should be ≤ 35 mmHg. An important postoperative problem is reperfusion of the pulmonary edema and occurs in approximately 10% of patients [61]. Lung injury can develop within the first 2 days of exhibiting hypoxemia and radiographic infiltrates in areas where endarterectomy has been done [63]. Treatment for this condition includes maintaining a SaO2 >90% and positive end‐expiratory pressures of 5–10 cm. Prostaglandin E1 at 0.01–1 mg/min and inhaled nitric oxide (20–40 parts per million) may be useful. Diuretics use is often required to reduce the incidence of pulmonary edema [64]. Since the reperfusion injury is neutrophil mediated, treatment with agents that block the selectin‐mediated adhesion of leucocytes to the endothelium (Cylexyn) could be useful [63]. Extracorporeal support has been used in selected patients with serious reperfusion injury [52]. Permanent anticoagulation with warfarin is started on the second postoperative day [60].
Experienced centers have a mortality that ranges from 4.4 to 21% [53, 64–68]. Risk factors commonly associated with mortality in the early postoperative period are RV failure related to residual pulmonary hypertension, reperfusion lung injury and CPB duration [10, 52, 53]. Survival rates are almost the same when comparing patients who underwent pulmonary endarterectomy alone with other patients with additional procedures (5.8 vs. 6.7%, respectively) [62]. In the largest study with patients undergoing pulmonary endarterectomy, the 6‐year survival rate was 75% (Figure 10) [69]. The most common causes of late death were recurrent pulmonary embolism and persistent pulmonary hypertension [69]. Hemodynamic outcomes after pulmonary endarterectomy for most patients are favorable [56, 64–67, 70–74]. The only long‐term study on hemodynamics after PEA observed persistent pulmonary hypertension in 24% of patients who had pulmonary vascular resistance of more than 500 dynes‐sec‐cm−5 after 4 years [75]. Dramatic reduction and, sometimes, normalization of the pulmonary artery pressure and pulmonary vascular resistance can be achieved. The mean reduction in pulmonary vascular resistance is approximately 65% [52]. Most patients are in New York Heart Association Functional Classification, class III or IV, before surgery; after the procedure, they can improve to class II or I and are able to resume normal activities [11, 69, 70]. Recurrent thromboembolism requiring a second endarterectomy has occurred in several patients in whom anticoagulation was discontinued or given improperly [76].
Survival after pulmonary thromboendarterectomy in 532 patients. Adapted from Archibald et al.
CTEPH is a life‐threatening complication of pulmonary embolism. There are notable differences in the treatment from that of other forms of pulmonary hypertension. A complete diagnostic assessment should be done in those patients with unexplained pulmonary hypertension. These studies should include a ventilation‐perfusion scintigraphy, right‐heart catheterization and pulmonary angiography. It is recommended though that the final diagnostic and therapeutic approach should be performed in experienced centers.
PEA is the preferred treatment and remains the only potentially curative approach. For patients in whom surgery is not an option, riociguat is the only approved drug that improves hemodynamics and exercise capacity. Balloon pulmonary angioplasty is yet to be proven effective in the treatment of these patients. An increased understanding of the prevalence of this condition and opportunities of surgical cure should benefit a larger volume of patients.
Gastric cancer is the second most common cause of cancer-related death worldwide [1]. Radical operation is the main treatment for gastric cancer, but the recurrence rate following surgery is high due to the early dissemination of cancer cells via the lymphatic system (about 40–80% in advanced gastric cancer) [1, 2]. In East Asia, especially Japan and Korea, D2 lymph node dissection is the standard treatment for operable gastric cancer [3, 4]. However, in the Western world, D2 gastrectomy is not as widely performed as in Japan and Korea [5]. Western surgical studies have shown that most patients present with tumors that penetrated the submucosa; they have a 5-year survival rate of 20–30% [6]. Postoperative chemotherapy is a standard treatment component of resectable gastric cancer and has improved patient outcomes [3, 4]. Treatment results of adjuvant chemotherapy may depend on the interaction between residual cancers and anticancer drugs. The Japanese recommendation for adjuvant chemotherapy is based on the Adjuvant Chemotherapy Trial of TS-1 for Gastric Cancer (ACTS-GC) study, which showed a survival benefit with adjuvant chemotherapy after D2 gastrectomy compared with surgery alone [4]. This study showed a survival benefit for stage II and IIIA gastric cancer [4]. However, the FLAGS trial for advanced gastric cancer or gastroesophageal cancer that compared cisplatin and S-1 versus cisplatin and fluorouracil in non-Asian countries did not prolong overall survival [7]. In Korea, adjuvant immunochemotherapy in advanced gastric cancer patients, who had undergone radical subtotal gastrectomy for stage III gastric cancer has been performed. For immunotherapy, a Streptococcus pyogenes preparation (picibanil) was followed by MF (mitomycin C and 5-FU) in the late 1990s and early 2000s [3, 8]. The Capecitabine and Oxaliplatin Adjuvant Study in Stomach Cancer (CLASSIC) study was designed to compare the effect of adjuvant capecitabine plus oxaliplatin after D-2 gastrectomy with stage II or III gastric cancer [1]. Although adjuvant chemotherapy is a standard treatment option for operable gastric cancer, there have been some differences concerning methods of chemotherapy and survival data between the Western world (Europe and North America) and East Asia (Korea and Japan). Therefore, this article summarizes the adjuvant chemotherapy for resectable gastric cancer using a medical literature review.
Treatment results of adjuvant chemotherapy may depend on the interaction between residual tumor and anticancer drugs. The tumor burden should be reduced as much as possible to obtain the most optimal survival benefit of adjuvant chemotherapy [10]. As compared to Western countries, the high survival rate in East Asia might have resulted from a selection of early-stage patients and radical operations, including systematic lymph node dissection [10]. The Southwestern Oncology Group (SWOG) conducted a two-armed prospective, randomized trial of adjuvant chemotherapy for patients with gastric adenocarcinoma surgically resected to negative margins (Table 1). Most patients (54%) had undergone a D0 dissection, which is less than a complete dissection of the N1 nodes. The chemotherapy regimen included fluorouracil, 425 mg/m2 of body-surface area per day, and leucovorin, 20 mg, followed by radiotherapy of 4500 cGy of radiation at 180 cGy/day. The median survival time in the surgery group was 27 months as compared with 36 months in the chemoradiotherapy group [5]. The 3-year survival rates were 50% in the chemoradiotherapy group and 41% in the surgery-only group [5, 11]. The 503-patient United Kingdom National Cancer Research Institute (NCRI) Medical Research Council Adjuvant Gastric Infusional Chemotherapy (MAGIC) trial was the first randomized trial to demonstrate the survival benefit from the use of perioperative chemotherapy for patients with resectable gastric cancer compared with surgery alone. The patients who received perioperative chemotherapy with the ECF regimen (epirubicin, cisplatin, and 5-fluorouracil, 5FU) had a 5-year survival of 36%, compared with 23% in patients treated with surgery alone [12] (Table 1). Kim et al. evaluated 10,783 consecutive patients who underwent operation for gastric cancer [3]. The prognostic significance of treatment modality (surgery alone, surgery + chemotherapy, surgery + immunotherapy + chemotherapy <immunochemotherapeutic treatment>) was evaluated for stage III gastric cancer. The protocol for immunochemotherapy was as follows: Picibanil (a Streptococcus pyogenes preparation; Tokyo, Japan), mitomycin C 4 mg/50 kg, and 5-FU 500 mg/50 kg. They concluded that radical lymph node dissection, with more than 25 resected lymph nodes, improved survival in patients with stage II and IIIc disease; as postoperative adjuvant therapy, immunochemotherapy was most effective in patients with stage III disease. There were significant differences in survival in stage III patients; the 5-year survival rates were 44.8% for the immunochemotherapy group, 36.8% for the surgery + chemotherapy group, 36.8% for the surgery + chemotherapy group, and 27.1% for the surgery-alone group [3]. In the meta-analysis, which assessed entitled adjuvant chemotherapy after curative resection for gastric cancer in Non-Asian patients, Earle et al. concluded adjuvant chemotherapy may produce a small survival benefit of borderline statistical significance in patients with curatively resected gastric carcinoma [13]. Sakuramoto et al. reported that patients with stage II or III gastric cancer who underwent gastrectomy with extended (D2) lymph node dissection were randomly assigned to undergo surgery followed by adjuvant chemotherapy with S-1 or to undergo surgery only. The analysis of the follow-up data showed that the 3-year overall survival rate was 80.1% in the S-1 group and 70.1% in the surgery-only group [4]. Consecutive results of the ACT-GC trial showed the overall survival rate at 5 years was 71.1% in the S-1 group and 61.1% in the surgery-only group (Table 1) [9]. In the Capecitabine and Oxaliplatin Adjuvant Study in Stomach Cancer (CLASSIC) trial, the patients with stage II–IIIB gastric cancer who had curative D2 gastrectomy were randomly assigned to receive adjuvant chemotherapy of eight cycles of oral capecitabine (1000 mg/m2 twice daily on days 1–14 of each cycle) plus intravenous oxaliplatin (130 mg/m2 on day 1 of each cycle) for 6 months or surgery only. The 3-year disease-free survival was 74% in the chemotherapy and surgery group and 59% in the surgery-only group. They concluded that adjuvant capecitabine plus oxaliplatin treatment after curative D2 gastrectomy should be considered as a treatment option for patients with operable gastric cancer [1].
Study | Regimen (surgery + chemotherapy surgery alone) | No. of patients | 3-YSR (%) | 5-YSR (%) |
---|---|---|---|---|
Macdonald et al. [5] | 5FU + leucovorin + radiotherapy | 281 | 50 | 40 |
Control | 275 | 41 | 30 | |
Cunningham et al. [6] | Epirubicin + cisplatin +5FU | 250 | 45 | 36 |
Control | 253 | 30 | 23 | |
Sakuramoto et al. [4, 9] | S-1 | 529 | 80 | 71 |
Control | 530 | 61 | 70 | |
Bang et al. [1, 2] | Capecitabine + oxaliplatin | 520 | 83 | 78 |
Control | 515 | 78 | 69 |
Adjuvant chemotherapy compared to the surgical control of curative resection of stomach cancer.
YSR, year survival rate.
Adjuvant chemotherapy is a standard treatment option for operable gastric cancer and improves patient outcomes, but the preferred treatment differs by geographical region [10]. The recommended adjuvant treatment is chemoradiotherapy in the United States and perioperative chemotherapy in the United Kingdom and some parts of Europe [1, 5, 12]. The Japanese ACT-GC trial was the first large-scale randomized trial of adjuvant chemotherapy after curative resection with D2 gastrectomy [4]. In the Republic of Korea, the CLASSIC trial was the second large-scale randomized trial after D2 gastrectomy [1]. The survival rate of two Asian large-scale randomized trials was substantially higher than in the US Intergroup-0116 and UK MAGIC trials (78% in the CLASSIC trial, 80% in ACT-GC vs. 30–40% in the Intergroup-0116 and MAGIC trials) [1, 4, 5, 12]. Most recurrences after surgery of gastric cancer occurred within 3 years of surgery [14]. The duration of adjuvant chemotherapy differed from previous studies. Kim et al. had adjuvant chemotherapy for 24 months [3]. The ACT-GC trial had adjuvant chemotherapy for 12 months [4]. CLASSIC trial had adjuvant chemotherapy 6 months [1]. The duration of adjuvant chemotherapy after surgery was different, although similar survival results were present in two clinical trials. Kim et al. reported that radical lymph node dissection, with more than 25 resected lymph nodes, improved survival in patients with stage II and IIIa disease [3]. Postoperative immunochemotherapy was most effective in patients with stage II and III disease [3]. The favorable outcomes of Asian studies were a result of the consistent adoption of D2 gastrectomy and the quality control of surgery using video techniques [1, 4]. But postoperative chemoradiotherapy in the United States and perioperative chemotherapy in Europe is not based on D2 gastrectomy. In the Intergroup-0116 study, quality assessment was done for radiotherapy before the initiation of this treatment [5]. However quality control of surgery was not done, because patients were usually identified postoperatively, and they could not require specific surgical procedures. Only 10% of the patients underwent a D2 dissection, while 36% had a D1 dissection, and 54% had a D0 lymphadenectomy (a resection in which not all of the N1 nodes were removed) [5]. The low long-term survival rate of stomach cancer patients in Western studies might result from excessive residual tumor left behind during surgery. The high survival rate in countries such as South Korea and Japan might be the reflection of the small amount of residual tumor due to radical gastrectomy and extensive lymph node dissection [10]. Songun et al. [15] reported that after a median follow-up of 15 years, D2 lymphadenectomy with strict quality control is associated with lower locoregional recurrence and gastric cancer-related death rates in patients with stage II and IIIa disease than D1 surgery; they recommended D2 resection as the standard surgical approach to resectable gastric cancer [15]. The CLASSIC and ACT-GC trials showed the effectiveness of postoperative adjuvant chemotherapy with S-1 and XELOX for stage II and III gastric cancer patients who underwent D2 gastrectomy [1, 4]. Biological aspects may cause the different gastric cancer results between East Asia and the Western world. However, no significant differences in prognostic factors were reported between these two regions of the world. In conclusion, for all patients with stage II and III gastric cancer worldwide, standard D2 gastrectomy and adjuvant chemotherapy are strongly recommended for a better rate of survival.
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