Gastric cancer represents a serious health problem on a global scale. It is the second leading cause of cancer-related death worldwide. Novel therapeutic targets are desperately needed because the meager improvement in the cure rate of about 10 percent realized by adjunctive treatments to surgery is unacceptable as more than 50 percent of patients with localized gastric cancer succumb to their disease.
Either postoperative chemoradiotherapy (in the United States), pre-and post-operative chemotherapy (in Europe), and adjuvant chemotherapy after a D2 resection (in Asia) can all be regarded as standards of care in the localized management of the disease. For patients with metastatic disease, the addition of trastuzumab to chemotherapy is standard of care in HER2-positive disease. In the HER2-negative population, the treatments remain limited.
In the first-line setting, the standard of care is a combination of fluoropyrimidine and platinum-containing chemotherapy, with or without epirubicin or docetaxel. Finally there is a minimal overall survival benefit in treating patients with metastatic disease in the second-line setting, with either irinotecan, docetaxel, or ramucirumab with or without chemotherapy.
Our approach to the treatment of patients with gastric cancer begins with appropriate clinical staging to determine if the cancer is localized or advanced. This involves full imaging, including CT of the chest/abdomen/pelvis, PET-CT, endoscopic ultrasound (EUS), and finally a staging laparoscopy.
EUS is the most reliable nonsurgical method to evaluate the depth of invasion, with concurrent evaluation of regional lymph nodes of primary gastric cancers and is therefore instrumental; however, things are not as simple as doing an EUS because this technique is really only useful in the hands of a skilled operator.
The PET/CT scan is most useful in detecting occult distant metastasis, thereby helping avoid high morbidity surgery in a sub-group of patients. Laparoscopy should be considered for patients who appear to have locoregional disease (other than stage IV, Tis or T1a stage) after conventional radiographic and EUS staging. However, because it is sometimes difficult to differentiate T2 and T3 lesions on EUS, it is reasonable to perform a laparoscopy for any medically fit patient who appears to have more than a T1 lesion on EUS, no histologic confirmation of stage IV disease, and who would not otherwise require a palliative gastrectomy because of symptoms. This is because 20 to 30 percent of patients with greater than T1 EUS disease will be found to have peritoneal metastasis despite having negative CT and PET scans.
In our center the clinical staging is followed by a multidisciplinary discussion in all localized gastric cancer cases:
Localized Gastric Cancer
In terms of localized gastric cancer, a curative resection (R0) offers the best chance of cure, and is best managed at high-volume centers and by high-volume surgeons. We strongly believe that a multidisciplinary approach and preoperative therapy is the cornerstone of management in the West.
Although gastrectomy is the recommended treatment in relatively early-localized gastric cancer (T1b), in more advanced disease (T2N0, T1aN+, or T1b-T3N+) we recommend adjunctive therapy in addition to gastrectomy. As previously mentioned, postoperative chemoradiotherapy (United States), pre-and post-operative chemotherapy (Europe), and adjuvant chemotherapy after a D2 resection (Asia) can all be regarded as standards of care in the management of localized gastric cancer. However, at our institution, we use a combination of these approaches in the pre-operative setting, because in our experience post-operative therapy is much harder to deliver.
Our general approach is to start with pre-operative chemotherapy with a platinum-based doublet or triplet (depending on the performance status of the patient) for two to three months, followed by chemoradiation also given preoperatively with 5-fluorouracil ± taxanes or platinum, finally followed by surgery. This approach is based on Phase II study data and results in R0 resection in 70 to 78 percent of our patients and five-year overall survival rates at least comparable to those reported in the Intergroup 0116 and MAGIC clinical trials.
In terms of post-treatment surveillance, there is no data to provide guidance, and arbitrary surveillance strategies are used.
Metastatic Gastric Cancer
In terms of our approach to metastatic gastric cancer, clearly in the context that this is no longer a curative situation our approach is to the palliation of symptoms and prolongation of life:
Otherwise, we would treat differently based on HER2 status. Clearly in HER2-positive gastric cancer there is an overall survival benefit to the addition of anti-HER2 therapy to first line chemotherapy.
It is our practice to typically use trastuzumab and not lapatinib because of the negative results of the lapatinib trial in combination with platinum-based doublet. Although no convincing data exists as to the benefit of the addition of HER2 therapy in gastric cancer, we extrapolate from the breast cancer trials and continue anti-HER2 therapy beyond progression, typically switching to an alternative agent such as pertuzumab.
In the context of HER2-negative metastatic disease, our options continue to be limited. In a select subgroup of patients who have small-volume disease and who are asymptomatic, a careful watch-and-wait strategy is reasonable as long as the patient is comfortable with this approach. In symptomatic patients, a reasonable option in the first-line setting is a platinum-based doublet with the addition of docetaxel or epirubicin, depending on the performance status of the patient or clinical trials.
In the second-line setting, we often use irinotecan-based doublets, but with the recent approval of ramucirumab, this agent in combination with chemotherapy will have a role in our practice.
Genetic profiling of tumors is becoming a more widely used tool in the treatment of gastric cancer, as it is in other cancers. Patients are often found to have multiple and even more often non-targetable mutations. Even when a potentially targetable mutation is found and the patient is treated with a given drug, we have found that responses are rare--likely because of our poor knowledge of driver mutations. Therefore we do not consider a genetic evaluation a critical part of treatment, but rather emphasize the enrollment of patients into available clinical trials.
In summary, we strongly feel that all patients with localized gastric cancer in a potentially curable situation should be evaluated in a multidisciplinary way and in a high-volume center, so that they can have the benefit of a surgery performed by a high-volume surgeon. In metastatic disease at our institution we put emphasis of enrollment of patients on clinical trials in hopes of improving outcomes.
The authors are all from the University of Texas MD Anderson Cancer Center: Elena Elimova, MD, MSC, Department of Gastrointestinal Medical Oncology; Brian Badgwell, MD, Department of Surgical Oncology; Prajnan Das, MD, MS, MPH, Department of Radiation Oncology; Jeannelyn Estrella, md, Department of Pathology; Aurelio Matamoros Jr., md, Department of Diagnostic Radiology; and Jaffer A. Ajani, md, Department of Gastrointestinal Medical Oncology.