We discuss briefly the treatment of gastric cancer depending surgical resectability and the presence of distant metastases.
Surgically Resectable Disease
Surgery
Surgery is the mainstay of gastric cancer treatment with curative intent, with the procedure of choice depending on patient and tumor characteristics.
Endoscopic mucosal resection or endoscopic submucosal dissection is appropriate for the treatment of favorable early-stage gastric cancer based on depth of invasion (Tis or T1a), size (2cm maximum), pathology (well or moderately-well differentiated), and the absence of ulceration or lymphovascular invasion [37]. Patients meeting these criteria have a <5% chance of LN metastases, so LN dissection may be omitted [16]. Those with less favorable early-stage disease who are unfit for surgery are also candidates for endoscopic resection [37].
Because gastric cancers are usually more advanced at the time of diagnosis in Western countries, gastrectomy with lymph node dissection is far more commonly offered to those treated with curative intent. Multimodal therapy should be considered for T2+ or node-positive disease.
For distal tumors that are at least 6cm removed from the gastric cardia, distal gastrectomy is preferred for being less morbid while maintaining similar survival rates to total gastrectomy [38]. The morbidity benefits of proximal gastrectomy for more proximal tumors over total gastrectomy are less established. As such, proximal tumors are typically managed with total gastrectomy, although proximal gastrectomy may be considered in select patients [37]. Regardless of technique, an attempt should be made to achieve negative margins at least 4cm from the gross tumor.
The optimal extent of lymph node dissection during gastrectomy is controversial. A discussion of the merits of the various levels of lymph node dissection is beyond the scope of this module. Readers interested in details are referred to the guidelines published by the National Comprehensive Cancer Network (NCCN) and the Japanese Gastric Cancer Association, as well as original literature on the topic. The number of nodes that are dissected is important for accurate staging and possibly survival, with a recommended minimum of 15-16 lymph nodes [7, 37, 39].
Multimodal therapy
The effectiveness of multimodal therapy has been demonstrated across multiple trials. Supplementing surgery with chemotherapy or radiation therapy should be strongly considered for all T2+ or node-positive disease [37]. Regimens that have shown superiority to surgery alone include:
- Perioperative epirubicin, cisplatin, and fluorouracil (ECF) [40]
- Perioperative cisplatin and fluorouracil (CF) [41]
- Adjuvant S-1 [42]
- Adjuvant capecitabine and oxaliplatin (CAPOX) [43]
- Adjuvant fluorouracil and leucovorin-based chemoradiotherapy [44, 45]
Neoadjuvant chemoradiotherapy, whose use was extrapolated from esophageal cancer, has also shown promising early results for gastric cancer [37, 46]. Recently, perioperative fluorouracil, leucovorin, oxaliplatin, and docetaxel (FLOT) has gained traction after it was demonstrated to improve survival over ECF [47]. Finding the optimal sequence and combination of multimodal therapy remains an area of active research, with many variations currently under investigation.
Nonmetastatic unresectable or medically inoperable patients
Literature on the treatment of locally advanced disease is limited. Fluorouracil-based chemoradiotherapy appears to be more effective than either chemotherapy or radiotherapy alone in two older trials [48, 49]. For medically fit patients, chemoradiation may increase the likelihood of conversion to resectable disease [37]. The alternative is combination chemotherapy alone, as with metastatic disease discussed henceforth.
Metastatic Disease
Chemotherapy is the cornerstone of treatment for patients with advanced gastric cancer. Compared to supportive care, chemotherapy has been found to improve quality of life and prolong survival from 4.3 to 11 months [50]. Two-agent chemotherapy, which extends survival compared to single-agent chemotherapy, is recommended for most patients [37, 50]. The combination of a fluoropyrimidine (e.g. 5-fluorouracil or capecitabine) and a platinum agent (e.g. cisplatin or oxaliplatin) is considered first line, although several alternative regimens have also shown promising results [37]. Combination chemotherapy with three cytotoxic drugs further prolongs survival and increases response rates, albeit with greater toxicity; these regimens may be appropriate as first-line treatment for select medically fit patients with good performance status [37, 50].
A number of targeted therapies have emerged with encouraging results in specific patient populations over the past decade [51, 52, 53]. Health Canada has approved trastuzumab and ramucirumab for HER2-overexpressing and previously-treated patients with advanced gastric cancer, respectively. Other targeted therapies are also showing promising early results, including FDA-approved pembrolizumab for select MSI-H/dMMR tumors [37].
There is conflicting evidence on the aggressive management of oligometastatic gastric cancer with surgery or radiotherapy directed at either the primary or metastatic deposits [56-62]. The only phase III trial completed to date, conducted in East Asia, did not find benefit in adding gastrectomy to chemotherapy [61]. Ongoing RCTs will hopefully shed further light on this subject (RENAISSANCE, NCT03161522) [63]. The management of oligometastatic gastric cancer is dependent on center of practice. A comprehensive discussion on this subject is beyond the scope of the module; however, relevant features include:
- Patient’s age, health, performance status
- Number and volume of metastases
- Location of metastases (para-aortic nodes, lung, liver are some potential candidates considered more amenable to surgery)
- Timeline: metachronous versus synchronous
- Basis of diagnosis
- Primary tumor status (controlled versus uncontrolled)
- T and N stage
- Local expertise and resources
- Palliative Treatment
Radiotherapy is effective for local palliation, with more than two-thirds of patients experiencing bleeding, pain or obstruction responding to therapy. Concurrent chemoradiotherapy is associated with significantly higher toxicity than radiotherapy alone, but there is a lack of evidence comparing local outcomes [55]. The benefits to chemotherapy on survival are, however, well established. Other options used to control local symptoms include endoscopic treatment, interventional radiology, medical therapy (e.g. proton pump inhibitors), stenting, and stenting [37]. In view of the significant heterogeneity in this population, there are unsurprisingly few studies comparing the effectiveness of different modalities. A multidisciplinary approach is especially critical for this diverse group of patients.
