Current management of gastric cancer

Situación actual en el tratamiento del cáncer gástrico

Antonio Viúdez-Berral¹, Coro Miranda-Murua², Fernando Arias-de-la-Vega³, Irene Hernández-García¹, Alicia Artajona-Rosino², Álvaro Díaz-de-Liaño² and Ruth Vera-García¹

¹Department of Medical Oncology, ²Area of Surgery, Unit of Esophagogastric Surgery, and ³Department of Radiotherapy. Complejo Hospitalario de Navarra. Pamplona, Spain

Correspondence

ABSTRACT

Gastric cancer is a disease with high incidence and mortality in our population. The prognosis of patients with this disease is closely related to the neoplasm stage at diagnosis, including the following characteristics of the tumor: extension into the gastric wall thickness, spread to locoregional lymph nodes and the ability to generate distant metastases, as described by the TNM classification.
For localized tumors characterized only by invasion of mucosa or submucosa at diagnosis, survival at 5 years is between 70 and 95% with exclusive surgical management; however, when extension into the gastric wall is higher and/or there is locoregional nodal involvement, survival decreases to 20-30% at 5 years.
Currently, at high-volume centers, the extent of gastrectomy is individualized based on several parameters, which in an increasing number of cases allows a total gastrectomy with D2 lymphadenectomy and preservation of the spleen and pancreas. This improved procedure increases the chance of R0 surgery and improves the relationship between resected and affected lymph nodes, resulting in a decreased risk of the long-term locoregional recurrence.
To improve these results, different therapeutic strategies combining chemotherapy or chemoradiotherapy with surgery have been tested. Previously, the Intergroup 0116 clinical trial, published in 2001, which changed clinical practice in the United States, showed that adjuvant chemoradiotherapy improved survival (from 26 to 37 months overall survival) of these patients. In Europe, perioperative chemotherapy has been considered the standard treatment, since the publication of two randomized phase III trials showed an increase at 5 years survival in the group treated with chemotherapy.

Key words: Gastric cancer. Gastric cancer surgery. Perioperative chemotherapy. Adjuvant chemotherapy. Adjuvant chemoradiotherapy.

RESUMEN

El cáncer gástrico es un tumor de alta incidencia y mortalidad en nuestro medio, y su pronóstico está íntimamente relacionado con la situación neoplásica al diagnóstico, que incluye su extensión en el grosor de la pared gástrica, sobre los ganglios linfáticos locorregionales y su capacidad de generar metástasis a distancia, extensión basada en la clasificación TNM.
En aquellos tumores localizados al diagnóstico, caracterizados por la invasión únicamente de mucosa-submucosa, la supervivencia a 5 años se establece entre el 70 y el 95% con manejo quirúrgico exclusivo, sin embargo, cuando la extensión en la pared es mayor y/o existe afectación ganglionar locorregional, la supervivencia disminuye al 20-30% a 5 años. ]]> Actualmente en centros con alto volumen de pacientes, la extensión de la gastrectomía se individualiza en función de varios parámetros, optándose, en cada vez más casos, por la realización de una gastrectomía total con linfadenectomía D2 y preservación esplenopancreática, pues esta aumenta las posibilidades de conseguir una cirugía R0 y mejora la relación entre ganglios resecados y ganglios afectados, lo que se traduce en una disminución del riesgo de recidiva locorregional a largo plazo.
Con el objetivo de mejorar estos resultados, se han ensayado distintas estrategias terapéuticas de quimioterapia o quimiorradioterapia asociadas a la cirugía. Entre todas ellas destaca el ensayo 0116 del intergroup, publicado en el 2001, que cambió la práctica clínica asistencial en Estados Unidos, ya que demostró que un tratamiento de quimiorradioterapia tras la cirugía mejoraba la supervivencia (de 26 a 37 meses de mediana) de estos pacientes. En Europa es la quimioterapia perioperatoria el tratamiento estándar habitual, desde que se publicaron dos estudios aleatorizados fase III que demostraron un aumento en la supervivencia a 5 años en el grupo tratado con quimioterapia.

Palabras clave: Cáncer gástrico. Cirugía del cáncer gástrico. Quimioterapia perioperatoria. Quimioterapia adyuvante. Quimiorradioterapia adyuvante.

Introduction

During the second half of the last century, gastric cancer has been the most commonly diagnosed gastrointestinal tract tumor in both sexes. Currently, with the increased incidence of colorectal tumors, gastric cancer is now second in both mortality and incidence in developed countries. There are large geographic variations in distribution, between countries and in the regions within them (1). Gastric cancer is diagnosed twice as frequently in men (2).

In 2006, Spain had an estimated rate of 23.04 cases per 100,000 people, which was slightly higher than the EU average. However, when analyzing mortality in Spain, this tumor is fifth in men (behind lung cancer, colorectal, prostate and bladder cancer) and in women (after breast, colorectal, lung and pancreatic cancer). According to the latest data published by the Spanish Statistics Institute (INE), in 2006 gastric cancer was the leading cause of death in 3,544 men and 2,178 women, representing an age-standardized rate in Spain of 13 per 100,000 in men and 5.5 in women. Is also poor, lower than 28% at 5 years in our country (3).

Further, analysis of the mortality time trend has shown a sharp decline since 1975, at 3% annually, with a fairly similar pattern in men and women. The geographic distribution of this tumor is characteristic within the state, and there are significant regional differences. Despite the decline in mortality that occurred over the last decades in practically all provinces, the pattern continues to be "coast-interior" (4). Thus, the rates for Castilla-León and towns on the coast of Galicia are among the highest in Europe.

The factors known to contribute to the worldwide gastric cancer epidemic are related to socioeconomic status; therefore, the decline in incidence and mortality rates associated with this disease can be interpreted as a consequence of the development of industrialized countries. Socioeconomic status is related to exposure to different factors, including diet, Helicobacter pylori infection, tobacco, and certain occupational exposures. However, a country like Japan having very high rates of stomach cancer indicates that socioeconomic status is not a single variable that adequately accounts for all exposures that increase the risk for gastric cancer. Thus, cultural factors inherent to different lifestyles, including diet, are likely to have considerable importance. This would also help to explain the substantial differences observed between some provinces in Spain. Other risk factors associated with this tumor include a history of partial gastrectomy, previous family history of gastric cancer, pernicious anemia, type A blood and exposure to ionizing radiation (5).

The main oncologic treatments of gastric carcinoma are based on surgery, systemic therapy and radiotherapy. Additionally, active palliation treatments are an important part of cancer management, including stents, surgical shunts and supportive measures. The management of gastric cancer requires a multidisciplinary approach (1).

Management of resectable disease

In our population at the time of diagnosis, only 40% of patients were diagnosed with resectable disease. In these cases, which were surgically treated, only one third were defined as an early stage (IA and IB); histological analysis of the remaining surgical specimens showed disease that, although resectable, was considered locally advanced (II, III, M0). The other 60% of patients were not candidates for surgery; half displayed locally advanced unresectable disease, and the other half displayed metastatic disease (6).

Overall, 60% of patients in whom complete surgical resection was achieved (R0) will relapse. Therefore, in absolute terms, the surgery is only curative 60% of the time.

The site of recurrence is locoregional in 70% of cases, peritoneal in 25-50%, hepatic in 30% and extra-abdominal in 30-50%. Various groups have attempted to lower the recurrence rates by adding various complementary treatments, either after surgery (adjuvant chemo and chemoradiotherapy), before surgery (neoadjuvant chemo and chemoradiotherapy) or before and after surgery (perioperative chemotherapy).

Surgical treatment

Preoperative staging aims to determine the extension of the disease in order to establish a personalized treatment plan. It is based on the guidelines set by the 7^th edition of the TNM classification supported by the UICC and AJCC in 2010.

The stage in groups according to this classification is shown in table I.

Preoperative diagnosis is based on the confirmation of the disease and the diagnosis of its extension. Endoscopy with biopsy is the test that allows histological confirmation of malignancy. The reliability of endoscopic ultrasound depends on the specialist who performs it (7). This test can have sensitivity for clinical T staging between 65-92% and for N stage between 50-95% and can result in a change in therapeutic management in approximately 25% of cases (8). CT (computed axial tomography) is used for the diagnosis of distant spread of the disease, with a sensitivity for clinical T staging between 43-82%. PET has not shown adequate sensitivity in the preoperative diagnosis of gastric carcinoma; however, it may be useful in association with CT (9).

Exploratory laparoscopy is a preoperative procedure used to classify potentially resectable patients, especially those undergoing neoadjuvant therapy, patients with unexplained elevated markers and patients with linitis plastica. These are several studies that estimate that the possibility of diagnosis of advanced disease with laparoscopy is approximately 30% (10).

The goal of surgery is the complete resection of disease and locoregional lymph nodes as well as the reconstruction of digestive continuity with maximum safety and minimal complications and/or sequelae. The type of treatment is established by consensus within multidisciplinary units, depending on the anatomic location of tumors, preoperative staging and the comorbidity associated with each patient (1).

Surgically unresectable tumors are those with level 3 or 4 histologic lymph node involvement, according to the Japanese Research Society of Gastric Cancer (11), invasion of major vascular structures and distant metastasis as well as liver and/or peritoneal spread (including positive peritoneal cytology).

According to the UICC, radical surgical treatment aims to remove the entire tumor, resulting in no trace of microscopic disease; this is called R0 surgery and is associated with better control of long-term disease. Surgical treatment is considered R1 when microscopic debris persists or R2 when macroscopic tumor remains.

Surgery with curative intention can be classified into four entities: a) standard resection; b) non-standard resection, in which the expanse of gastrectomy and/or lymphadenectomy was modified according to certain characteristics of the tumor; c) modified resection, which reduces the extent of gastrectomy and/or lymphadenectomy; or d) extended gastrectomy, which provides in bloc resection of adjacent organs or lymph node dissection that are dissected at the lymph node level above D2 (12). Palliative resection is applied only to the complications caused by the primary tumor, including relapse either in the form of bleeding or obstruction.

In antral tumors, subtotal gastrectomy has shown identical results in survival and mortality to those of total gastrectomy, with a lower complication rate and fewer nutritional disorders (13,14). The gastric cancer guidelines recommend treatment of gastric cancer with a macroscopic margin from the edge of the tumor to the stomach section of at least 5 cm (1,15,16). A microscopic involvement of resection margins is a factor for worse prognosis that increases risk of local relapse and thus lowers survival (17,18). Therefore, in the case of threatened margins into subtotal gastrectomy or total gastrectomy by cardial tumor, an intraoperative margins resection study was recommended.

Several randomized trials have shown that prophylactic resection of the spleen should not be performed because it morbidity without improvement in rates (19,20). In bloc resection of adjacent organs is only recommended when the tumor is directly invasive because this resection itself increases morbidity and mortality, which is only acceptable if R0 surgery is accomplished.

Lymph-node dissection levels are defined according to the JRSGC classification (11) and are also recommended by the AJCC and IUAC. This classification defines 16 nodal groups (Fig. 1): level 1 (N1), which includes the nodes from the lesser curvature (groups 1, 3, 5) and the greater curvature (groups 2, 4, 6) and level 2, which includes lymph nodes of the left gastric artery (group 7), common hepatic artery (group 8), celiac trunk (group 9), splenic hilum (group 10) and splenic artery (group 11). Notably, the latest edition of the Japanese Classification subdivides group 11 lymph nodes into "11p", defined as those from the origin of the splenic artery to mid pancreatic body, and "11d", defined as periarterial nodes from the mid-pancreatic body to splenic hilum (21).

Extension of the lymphadenectomy and preoperative definition of tumoral lymph node (22) are widely debated topics in literature due to their impact on survival and their use as quality control measure of surgical technique. To perform an adequate D1 lymphadenectomy, which is necessary for correct postoperative staging, a minimum of 15 nodes must be analyzed, and more than 20 when it performing a D2 lymphadenectomy (23).

Asiatic working groups have been the main promoters of the analysis of detailed lymph node dissections. In these countries total gastric resection with D2 lymphadenectomy is the treatment of choice. In a Japanese randomized controlled trial, JCOG9501, D2 lymphadenectomy was compared to extended D2 lymphadenectomy, including para-aortic nodal dissection (D3). The results of this study demonstrated that the five-year survival after extended lymphadenectomy was similar (70,3%) to that after D2 lymphadenectomy (69,2%), noting a higher morbidity in the first group (24). Another trial showed higher survival after D2 lymphadenectomy extended to para-aortic nodes compared with D1 lymphadenectomy only (25).

Paradoxically, these data published by Japanese researchers have not been reproduced by trials in Western countries. In the trial carried out by the British Cooperative Group that compared D2 with D1 lymphadenectomy, the five-year survival was similar (33 vs. 31%), though there was higher morbidity in the group in which a D2 lymphadenectomy was performed (26). Similar results were published by other groups (27-30). Among them, a trial carried out by the Dutch Gastric Cancer Group stands out. That study, which compared D2 with D1 lymphadenectomy, showed a higher morbidity (43 vs. 25%) and postoperative mortality (10 vs. 4%) in the D2 lymphadenectomy group, without differences in cumulative five-year survival (35 vs. 30%) (28). However, in that trial, a 15-year follow-up showed a lower rate of local recurrence and disease-related mortality in the D2 lymphadenectomy group compared to the D1 group. Importantly, there was a difference in patients with N2 involved nodes (19 vs. 0%) (31). Factors related to higher morbidity in the D2 group were above age 65 years old, male gender, type of gastrectomy and performance of a splenectomy and/or pancreatectomy. The increase in postoperative mortality secondary to splenopancreatectomy obscures the potential benefit of D2 lymphadenectomy over D1 (19,20,31). For this reason, different groups advocate D2 lymphadenectomy with splenopancreatic preservation to preserve 10 and 11d node stations, except for tumors in the greater curvature, to those that directly invade these organs or to those with metastatic nodes in these node stations. In the last guide from the Japanese Gastric Cancer Association in 2010, en-bloc splenectomy was considered only for clinical T2-T4 tumors invading the greater curvature or cardial tumors. It is not recommended for tumors of any other localization until conclusive results can be obtained from ongoing trials (16).

Laparoscopic resection of gastric tumors offers unquestionable benefits over open surgery, including less blood loss, better postoperative analgesic control, shorter hospital stays and quicker return to routine life. In this regard, a prospective European trial (32) and a Spanish meta-analysis (33) suggest similar results to the laparoscopic procedure in terms of survival and postoperative morbidity and mortality compared to the open procedure (30). However, more prospective trials are needed to gather a higher number of cases and obtain long-term results regarding disease control (34,35).

In our institution, the strategy of surgical treatment with curative intention in patients with distal tumors smaller than 3 centimeters in size without serosal invasion and with intestinal histology is subtotal gastrectomy. In the rest of cases, total gastrectomy with transit reconstruction with a defunctionalized Y-en-Roux limb is performed. In those clinically diagnosed with T1 tumors or in elderly patients, the selected gastric resection is associated with D1 lymphadenectomy. Finally, in those cases clinically T2-T4 or N(+), depending on age, the selected gastrectomy is performed along with a D2 lymphadenectomy with splenopancreatic preservation, with the exception of those cases previously discussed that involve the greater curvature, direct invasion of said organs or has nodal involvement of 10 and/or 11d nodal statios; in these cases, splenopancreatic resection becomes necessary (36).

Adjuvant chemotherapy

Systemic treatment of gastric cancer has led to the development of different treatment strategies in the West and East. The drugs used in Japan, Korea and other Asian countries have demonstrated a different kinetic behavior in Caucasian populations of the West (37). This is significant because polymorphism differences between the two populations affect the tolerability and efficacy of these drugs.

Adjuvant chemoradiotherapy

There have not been major developments following the publication in 2001 of phase III SWOG 9008/INT 0116 (46), in which 556 patients with adenocarcinoma of the stomach or esophagogastric junction (stage IB to IV-M0) subjected to curative resection, were randomized to surgery alone versus surgery followed by chemo-radiotherapy (5-fluorouracil bolus-5FU- plus leucovorin). In this study, it was observed that the application of adjuvant therapy resulted in a significant increase in disease-free survival and overall survival at 3 years. These results were confirmed after a follow-up of more than 10 years, with a HR of 1.32 (p = 0.004) for survival and 1.51 (p < 0.001) for disease-free survival. This benefit was maintained in all subgroups except in the diffuse histological subtype (47). The limitations of this study were focused on the type of surgery performed because in 54% of patients, this was suboptimal (less than D1 lymph node dissection), raising the question of whether postoperative chemoradiotherapy could have offset the low nodal resection in most cases. To clarify this issue, a subgroup analysis of the INT0116 trial was published in 2002 (48). This showed that the survival benefit of adjuvant chemo-radiotherapy remained similar in the D0 and D1 lymph node dissection groups, while survival benefits in the D2 dissection group were doubtful; however, the small number of patients in this last subgroup made it difficult to draw exhaustive conclusions. An observational Korean study on more than 500 patients (12) showed the benefit of adjuvant chemoradiotherapy even after D2 surgery. Studies have shown that the addition of more cytotoxic drugs to 5FU therapy, according to the MacDonald scheme, does not translate into a survival benefit (49,50).

The planning of radiotherapy fields requires experience and a quality assurance system. Radiotherapy is influenced by its conformation in 3D (3D-CRT) or intensity modulated radiotherapy (IMRT), and these technologies have been shown to reduce toxicities. A total radiation dose 45 Gy is set to run in 25 fractions of 1.8 Gy. The delimitation of volumes must meet the guidelines established by the RTOG and EORTC and include the tumor bed, celiac lymph nodes and para-aortic nodes.

Perioperative treatment

Following the publication of the final results of the English phase III MAGIC study (51), which showed an increase in cumulative survival at 5 years of 13%, many authors consider the classical ECF (epirubicin, cisplatin and 5FU) perioperative cocktail used in this study as the new standard treatment in this setting.

On the other hand, the ACCORD group presented the results of the FFCD 9703 study (52), which demonstrated that the administration of cisplatin and 5FU also increased perioperative progression-free survival (PFS) and overall survival in patients with resectable gastric adenocarcinoma compared with the control group. These results are very similar to those observed in the MAGIC study.

Two recent meta-analyses examined the role of neoadjuvant chemotherapy. In the first, a reduction in absolute risk of death at 5 years of 32% was observed in favor of neoadjuvant treatment (53). In the second, the decrease in risk of death at 5 years was lower (only 18%) at the expense of patients with tumors at the esophagogastric junction treated with preoperative therapy (54). Based on the results of the REAL-2 study, the substitution of cisplatin by oxaliplatin and 5FU by capecitabine ca be performed successfully (55).

Treatment of advanced disease

Advanced gastric cancer cases are defined as those in which the disease is unresectable, including either locally advanced disease (30% of cases) or metastatic disease (another 30%) and patients who have relapsed (60% of resected cases). Globally, approximately 84% of patients with gastric cancer have advanced disease over the course of their illness.

Palliative chemotherapy has a clear impact on survival when compared with the best supportive care (HR = 0.39, 95 CI: 0.28-0.52), generating further improvement in the quality of life of those patients who are treated. This benefit is observed mainly in patients with preserved functional status. Currently, no chemotherapy regimen can be considered standard (56-58), and thus, the choice depends essentially on the patient's profile.

Between 1997 and 2000, several studies showed that cisplatin-based regimens were superior to other schemes without cisplatin (59,60). Both CF (cisplatin/5FU) and ECF (4-epirubicin, cisplatin and 5FU) can be considered as reference regimens. These schemes provide radiological response rates, ranging between 20 and 40%, and very few complete responses (approximately 5%). Unfortunately, this benefit usually lasts for a short time, with median time to progression after approximately 4-5 months and a median survival of only 7-10 months. As noted above, this benefit is considered for patients with good performance status, despite the toxicity and inconvenience of treatment, especially with cisplatin schemes, which is significant.

The V-325 study (61) compared the DCF regimen (docetaxel, cisplatin and 5FU) with CF. The primary endpoint was the time to progression, and overall survival was emphasized among the secondary objectives. The study was positive for its main objective, whose median was 5.6 months in the TCF arm compared to 3.7 months in the CF arm. There were also statistically superior outcomes in the TCF arm with respect to survival, survival at 2 years and response rate. As for toxicity, grade 3-4 neutropenia, febrile neutropenia and diarrhea were more common than cisplatin/5FU in the TCF group. It is noteworthy that febrile neutropenia decreased from 30 to 12% in the TCF-treated group with the administration of colony stimulating factors. This toxicity requires essentially adding docetaxel in patients selected for their good performance status.

The REAL-2 study (62) compared four different schemes, replacing cisplatin with oxaliplatin and 5FU with capecitabine. There were no statistically significant differences in the response rates or progression-free survival. The EOX scheme (epirubicin, oxaliplatin and capecitabine) was superior to ECF in overall survival (11.2 vs. 9.9 months, p = 0.02). The response rates were 40.7, 46.4, 42.4 and 47.9% for the ECF, ECX, EOF and EOX therapy, respectively. Other studies have demonstrated the noninferiority noninferiority of capecitabine versus 5FU and oxaliplatin versus cisplatin (63).

In the TOGA study (64), 22.1% of the patients analyzed (810 patients) were positive for c-erb-2 (IHC 3+ or FISH+). Positivity was higher in the Lauren intestinal subtype (32%) and in tumors of the esophagogastric junction (32.2%). The combination of trastuzumab with chemotherapy in patients who were c-erb-2-positive gave a survival increase of nearly 3 months (13.8 vs. 11.1 months). That benefit was substantially greater in patients who were c-erb-2 IHC 2 + and FISH + and IHC 3 +. In these patients, a median survival of 16 months was achieved. This benefit also increased the radiological response rate and progression-free interval without further toxicity.

Second-line treatment

The application of a second line of treatment may be justified in patients with a consistently maintained performance status. Two randomized trials have assessed the role of second-line chemotherapy. The first, a German study, was stopped prematurely due to lack of recruitment. Even so, this study showed a survival benefit in patients treated with tri-weekly irinotecan (HR 0.48, 95% CI 0.23 to 0.92, p = 0.023) (65). The second was a Korean randomized study for which data have been recently presented. That study demonstrated the benefit of second-line irinotecan or docetaxel ((HR 0.64, 95% CI 0.466-0.86392, p = 0.009) (66). The identification of variables such as functional status, baseline hemoglobin, time to progression after first-line therapy (more or less than 6 months), levels of CEA and the number of metastatic sites (more or less than 3) help to establish the expected benefit of a second line treatment (67-69).

Acknowledgements

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Correspondence:
Antonio Viúdez-Berral.
Department of Medical Oncology.
Complejo Hospitalario de Navarra.
C/ Irunlarrea, 3.
31008. Pamplona, Spain.
e-mail: antonio.viudez.berral@navarra.es

Received: 10-11-11.
Accepted: 11-11-11.