State of the art of diagnosis and treatment of locally advanced gastric cancer

Introduction Gastric cancer is the fifth cancer in incidence and the third cause of cancer-related death worldwide. It’s incidence is higher in Eastern Europe, Eastern Asia and South America than in North America and Western Europe. Almost one million cases are diagnosed each year, resulting in around 750,000 deaths. In recent decades, a decrease in incidence has become apparent, especially in Western Europe and North America.

The most common risk factors are:

· Male gender.

· Helicobacter pylori infection.

· Tobacco use.

· Atrophic gastritis.

· Ménétrier’s disease.

· Diet: alcohol use, high-salt diet, processed meat, low fruit and vegetable intake.

· Obesity.

Approximately 10% of the gastric cancer cases present with familiar aggregation and around 1-3% are associated with inherited genetic predisposition.

Diagnosis Western patients are usually diagnosed once the disease becomes symptomatic (weight loss, dysphagia, dyspepsia, vomiting, early satiety, iron deficiency anemia). On the other hand, patients in Eastern countries are usually diagnosed at earlier stages, and several countries where the incidence of gastric cancer is high (Korea, Japan) have developed screening programs.

Diagnosis should be made on the basis of a gastroscopy with biopsy and the histology should be reported according to the World Health Organization (WHO) criteria.

Staging Initial investigations should include:

· Physical examination.

· Blood test: with assessment for iron deficiency anemia, renal and liver function and nutritional status.

· Endoscopy and biopsy.

· CT scan of thorax, abdomen and pelvis: for staging and detection of local and distant lymphadenopaties and metastatic disease or ascites. Nonetheless, the sensitivity of CT scan for lymph node staging varies between 62.5% and 91.9%.

· Endoscopic ultrasound (EUS): is useful to determine the extent of the tumor and provides assessment of the T and N stage. Is considered more accurate than CT for the diagnosis of malignant lymph nodes.

· PET-scan may be useful for detecting involved lymph nodes or metastasis but is not informative in mucinous or diffuse tumors.

· Laparoscopy and peritoneal washing may help diagnose occult radiological metastasis and should be considered in all stage IB-III cancers, being more beneficial for T3/T4 tumors. After all the investigations are carried out, staging should be performed according to the latest AJCC/UICC guidelines.

Treatment decision All patients with gastric cancer should be discussed within a Multidisciplinary Treatment Conference to determine a treatment objective that should take into account patient performance status and comorbidities, and tumor-specific characteristics (histological subtype, the extent of the tumor, etc.). The members should include surgeons, medical oncologists, radiologist oncologists, radiologists and pathologists.

Although surgical resection is considered the standard therapy, in the Western world, surgery alone is associated with a 5-year survival of less than 25%, and thus, it is insufficient in curing advanced gastric cancer patients. Combined therapies should be used in > stage T2N0 patients with gastric adenocarcinoma.

Perioperative chemotherapy Perioperative ECF (epirubicin, cisplatin and 5-fluorouracil) chemotherapy was demonstrated to improve 5-year survival from 23% to 36% in stage II and III gastric cancer treated with six cycles (3 preoperative and 3 postoperative) compared to surgery alone in the MRC MAGIC trial. Perioperative chemotherapy has been widely accepted as a standard of care in Europe and regimes with capecitabine instead of 5-FU may also be suggested as they avoid the red for a central venous access.

The data of the German FLOT-4 study shows that FLOT (docetaxel/5-FU/leucovorin/oxaliplatin) achieves a higher rate of complete pathological response compared to ECF/ECX (16% vs. 6%), improves 3-year overall survival (57% vs. 48%) and progression-free survival (30 vs. 18 months).

Based on this data, FLOT is accepted as the standard perioperative therapy for advanced gastric adenocarcinoma.

Data from the HER-FLOT study in which 4 cycles of FLOT + trastuzumab followed by 6 months of trastuzumab reveal a high pathological complete response (22%) in Her2+ patients. Several trials (EORTC INNOVATION and FLOT 6-PETRARCA) are assessing the use of trastuzumab ni Her2+ patients.

Surgery Surgery is the cornerstone of advanced gastric cancer treatment. For stage IB-III gastric cancer, gastrectomy is indicated. Subtotal gastrectomy may be performed if a macroscopic proximal margin of >5 cm can be achieved (8 cm in diffuse cancers).

On of the most debated topics in cancer gastric surgery has been the extent of the lymphadenectomy accompanying radical gastrectomy. Debate between the East (advocating for D2 lymphadenectomy) and the West (advocating for a more limited lymphadenectomy) were common in the surgical literature in recent years.

D1 resection implies the removal of the perigastric lymph nodes and D2 dissection implies the removal of the perigastric nodes plus those along the common hepatic artery, splenic arteries, celiac axis and left gastric artery (see lecture https://aischannel.com/society/classification-lymphadenectomies-gastric-cancer)

Consensus is that in Western countries, medically fit patients should undergo D2 dissection in specialised high-volume centres in order to achieve a morbidity lower than 15% and a mortality lower than 3%. Minimum lymph node yield should be 15 to allow a proper staging.

Laparoscopic surgery is associated with lower postoperative morbidity and reduce recovery time. Concerns existed regarding the possibility of a decreased lymph node yield but trials from Eastern countries have reported equivalent results for distal gastrectomy. Nonetheless, results for total gastrectomy are still lacking although a small RCT from China which included patients with total and distal gastrectomy could find no differences in the 5-year overall survival rate or in the 5-year disease free survival rate between open gastrectomy and laparoscopic gastrectomy with D2 dissection (Y. Shi et al, Surgery 2019).

Conclusions

· Gastric cancer is the fifth cancer in incidence and the third cause of cancer-related death worldwide.

· Diagnosis should be done by endoscopy with biopsy.

· Staging requires: blood test, CT scan, EUS and PET-scan.

· Treatment decision should be taken within an MDT.

· Perioperative therapy is recommended for stage IB disease (> T2N0).

· Surgery is the cornerstone of gastric cancer treatment, associated with D2 lymphadenectomy.

· Laparoscopic surgery may be a valid approach for locally advanced gastric cancer patients.