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  1. Nalley, Catlin

Article Content

An estimated 26,240 cases of stomach cancer will be diagnosed in 2018 and about 10,800 people will die from the disease (CA Cancer J Clin 2018; doi:10.3322/caac.21442).

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While the number of new cases of stomach cancer have declined in the U.S. over the last 10 years, according to the American Cancer Society, it is still very common in other parts of the world, particularly less developed countries, and is one of the leading causes of cancer-related deaths worldwide.


More than 50 percent of localized distal gastric cancer can be cured. However, according to the NCI, early-stage disease accounts for only 10-20 percent of cases diagnosed in the U.S. For the remaining patients who present with regional nodal or distant metastatic disease from either distal or proximal disease, survival rates are significantly inferior. Location is also important as the 5-year survival of patients with proximal gastric cancer is only 10-15 percent, the NCI reported. "Although the treatment of patients with disseminated gastric cancer may result in palliation of symptoms and some prolongation of survival, long remissions are uncommon."


"The lack of long-term survivors in this disease, outside of the earliest stage presentation, is one of the biggest challenges [of gastric cancer]," noted Maria C. Russell, MD, Surgical Oncologist at Winship Cancer Institute and Assistant Professor, Division of Surgical Oncology, Department of Surgery at Emory University School of Medicine, Atlanta. "Additional challenges include finding patients at an earlier stage; the extensive endoscopic, radiographic, and laparoscopic staging recommended; as well as getting all of the treatments into our patient to provide them with the most favorable long-term outcomes.


"All gastric cancer should be discussed in a multidisciplinary conference since management can vary widely depending on the patient and tumor characteristics," she continued. "Standard of care for all but the earliest of gastric cancers involves multimodality therapy consisting of surgery and/or chemotherapy and/or radiation."


Choosing the Right Approach

When choosing the right treatment approach for gastric cancer, the therapy team must consider each case carefully. "We really have to take into account the location of the tumor and the preoperative stage, as well as the performance status of the patient prior to considering resection," Russell emphasized.


"For instance, if a patient presents with an obstructive cancer, they may require operative intervention upfront instead of neoadjuvant chemotherapy," she explained. "Likewise, the management of gastric cancer is a long road, so the performance status of the patients often dictate the amount of therapy that we can provide."


Surgery is an integral part of any curative intent management for gastric cancer, Russell told Oncology Times. "Operations for these patients consist of a distal gastrectomy, subtotal gastrectomy, or total gastrectomy with appropriate lymphadenectomy for all. Radiation can be used with chemotherapy in a neoadjuvant approach, but is more commonly used in the adjuvant setting for patients with R1 or R2 resections."


Among early gastric cancer cases, only 40 percent are associated with symptoms and 80 percent of patients present with greater than T1 disease. Sixty-five percent of patients present as advanced cancers (T3, T4), 85 percent have lymph node metastases, and 40 percent are metastatic (Int J Surg Oncol 2017; doi:10.1097/IJ9.0000000000000011).


Very early gastric cancer-which is rare in the U.S.-is defined as an in situ tumor or a T1a lesion. Among patients who are not medically fit, endoscopic mucosal resection (EMR) or endoscopic submucosal dissection (ESD) can be considered, according to Russell.


"Patients who are medically fit with a T1a lesion can be considered for EMR, ESD, or surgery. The caveat is that these patients should have tumors which are less than 2 cm, well or moderately well differentiated, without lymphovascular invasion, and in whom all margins are free of tumor," she explained. "These patients must then undergo routine surveillance. Patients with T1b tumors should be taken to the operating room for definitive surgery.


"Any patient with a T2 or higher tumor or evidence of lymphadenopathy should be considered for 3 months of neoadjuvant chemotherapy followed by surgery and then an additional 3 months of adjuvant chemotherapy," she continued. This treatment approach is based on the MAGIC trial, Russell noted. "[The study] demonstrated an improvement in overall survival at 5 years from 23 percent to 35 percent with perioperative chemotherapy consisting of epirubicin, 5-fluorouracil, and cisplatin (N Engl J Med 2006;355:11-20).


"This has been extrapolated to other drug regimens as well," she said. "However, more recent data presented at ASCO 2017 demonstrated that a four-drug regimen consisting of docetaxel, oxaliplatin, and fluorouracil/leucovorin further increases both progression-free survival and overall survival in patients with resectable gastric cancer (J Clin Oncol 2017; doi:10.1200/JCO.2017.35.15_suppl.4004)."


Surgical Advances

In recent years, a number of changes have occurred in the surgical management of gastric cancer patients.


For instance, according to Russell, surgeons are involved in treatment planning from the outset of the disease. "We frequently perform diagnostic laparoscopy shortly after diagnosis to assess for radiographically occult disease within the peritoneal cavity," she explained. "This can be diagnosed as carcinomatosis or as positive peritoneal washings. Unfortunately, either one of these is considered stage IV disease with a poor long-term prognosis."


Another shift in the surgical management of gastric has been an increase in the utilization of laparoscopy and robotic surgery for these resections, which, according to Russell, "can potentially offer the patient shorter hospitalization and less pain. The focus on maintaining patient safety and adequate oncologic resection with negative margins and a D2 lymphadenectomy, however, is of paramount importance."


Given gastric cancer with peritoneal carcinomatosis is considered an end-stage disease, oncologists are looking for other treatment options, including the combination of cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC).


Recent data, presented at the 2018 Gastrointestinal Cancers Symposium, delved into the potential role of CRS and HIPEC among these patients (Abstract 8). Data was collected from 277 consecutive patients who were treated for gastric cancer with peritoneal carcinomatosis in 19 French centers from 1989 to 2014. Researchers compared 180 patients who underwent CRS and HIPEC and 97 who were treated with CRS alone. A Cox proportional hazards regression model with inverse probability of treatment weighting (IPTW) based on propensity score was utilized to assess the effect of HIPEC and account for confounding factors. Multivariate models and sensitivity analyses were also performed, researchers noted.


Findings showed that HIPEC was associated with improved overall survival on both multivariate and IPTW models. Median overall survival was 18.8 months in the HIPEC group compared to 12.1 months among patients in the CRS alone cohort, study author Pierre Emmanuel Bonnot, MD, reported. Three-year and 5-year overall survival was 26.21 percent and 19.87 percent, respectively, for HIPEC patients. Comparatively, 3-year and 5-year overall survival was 10.82 percent and 6.43 percent among patients who underwent CRS only.


Median disease-free survival was also higher for patients who received HIPEC in addition to CRS (13.6 months) compared to those who underwent CRS alone (7.8 months). Additionally, 3-year and 5-year disease-free survival for patients who underwent CRS and HIPEC was 20.40 percent and 17.05 percent versus 5.87 percent and 3.76 percent for patients who only received CRS, according to investigators.


"In selected patients with localized or limited peritoneal carcinomatosis from gastric cancer, HIPEC combined with CRS increases overall survival and disease-free survival without increasing postoperative mortality and morbidity and should be considered a viable therapy option for such patients," Bonnot noted.


"There is increasing interest in potentially offering cytoreductive surgery and hyperthermic intraperitoneal chemotherapy to patients with limited carcinomatosis who have a great response to chemotherapy," Russell told Oncology Times. "Although long-term survival in the U.S. has not yet been a reality, this is something of potential future interest in gastric cancer management."


Targeted Therapies

While surgery remains an integral part of the management of gastric cancer, other therapeutic approaches are on the horizon that show promise for this patient population.


For example, recent data supports the potential therapeutic power of immunotherapy among gastric cancer patients. A phase III trial of nivolumab versus placebo in chemotherapy-refractory gastric cancer found the addition of the PD-1 inhibitor improved overall survival (4.1 months vs. 5.3 months) as well as 1-year survival (11% vs. 27%) (Lancet 2017; doi:


Another trial studied the efficacy and safety of pembrolizumab among patients with previously treated gastric cancer (J Clin Oncol 2017; doi:10.1200/JCO.2017.35.15_suppl.4003). Findings showed responses among 11.6 percent of patients; investigators reported higher responses among PD-L1 positive patients (15.5%) compared to those who are PD-L1 negative (6.4%). Based on the results of this study, the FDA approved pembrolizumab for patients with chemotherapy-refractory PD-L1 positive, advanced gastric and gastroesophageal junction cancers.


"We are all really excited about more personalized medicine for this disease," Russell noted. "This is evident with some recent publications on patients with mismatch repair genes that may respond better to immunotherapy, as well as targeted therapy for gene mutations.


"If we can unlock the mystery of whose individual cancer responds to what specific treatment instead of the standard approach of a couple of chemotherapy options for everyone, this is really where we have the opportunity to make huge strides in the management of gastric cancer," she concluded.


Catlin Nalley is associate editor.


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